Compositions and methods of treating disease with fgfr fusion proteins

ABSTRACT

The invention provides FGFR fusion proteins, methods of making them, and methods of using them to treat proliferative disorders, including cancers and disorders of angiogenesis. The FGFR fusion molecules can be made in CHO cells and may comprise deletion mutations in the extracellular domains of the FGFRs which improve their stability. These fusion proteins inhibit the growth and viability of cancer cells in vitro and in vivo. The combination of the relatively high affinity of these receptors for their ligand FGFs and the demonstrated ability of these decoy receptors to inhibit tumor growth is an indication of the clinical value of the compositions and methods provided herein.

RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/048,841, filed Oct. 8, 2013, which is a divisional of U.S.application Ser. No. 13/227,398, filed Sep. 7, 2011, now U.S. Pat. No.8,580,936 B2, which is a divisional of U.S. application Ser. No.13/157,712, filed Jun. 10, 2011, now U.S. Pat. No. 8,173,134 B2, whichis a continuation of U.S. application Ser. No. 12/652,720, filed Jan. 5,2010, now U.S. Pat. No. 7,982,014 B2, which is a continuation of U.S.application Ser. No. 11/791,889, now U.S. Pat. No. 7,678,890 B2, whichis a national stage application of PCT Application No.PCT/US2006/028597, filed Jul. 24, 2006, which claims the benefit of U.S.Provisional Application Nos. 60/701,479, filed Jul. 22, 2005;60/729,401, filed Oct. 21, 2005; 60/757,398, filed Jan. 10, 2006; and60/800,005, filed May 15, 2006. Each of the above applications isincorporated by reference herein in its entirety for any purpose.

SEQUENCE LISTING

The present application is filed with a Sequence Listing in electronicformat. The Sequence Listing is provided as a file entitled“2015-10-07_01134-0005-07US_Sequence_Listing_ST25.txt” created on Oct.7, 2015, which is 753,723 bytes in size. The information in theelectronic format of the sequence listing is incorporated herein byreference in its entirety.

TECHNICAL FIELD

The present invention relates to fusion molecules comprising anextracellular domain of a fibroblast growth factor receptor (FGFR). Itrelates to polypeptide and polynucleotide sequences, vectors, hostcells, compositions, kits, and animals comprising FGFR fusion proteins.The invention also relates to methods of making and using FGFR fusionmolecules and variants and fragments thereof to diagnose, prevent,determine the prognosis for, and treat proliferative diseases, includingcancer and disorders of angiogenesis.

BACKGROUND ART

Fibroblast growth factors (FGFs) and their receptors (FGFR) are a highlyconserved group of proteins with instrumental roles in angiogenesis,vasculogenesis, and wound healing, as well as tissue patterning and limbformation in embryonic development. FGFs and FGFRs affect cellmigration, proliferation, and survival, providing wide-ranging impactson health and disease.

The FGFR family comprises four major types of receptors, FGFR1, FGFR2,FGFR3, and FGFR4. These receptors are transmembrane proteins having anextracellular domain, a transmembrane domain, and an intracytoplasmicdomain. Each of the extracellular domains contains either two or threeimmunoglobulin (Ig) domains. Some FGFRs exist in different isoformswhich differ in specific segments of the molecule, such as FGFR1-IIIband FGFR1-IIIc, which differ in the C-terminal region of the third Igdomain. Transmembrane FGFRs are monomeric tyrosine kinase receptors,activated by dimerization, which occurs at the cell surface in a complexof FGFR dimers, FGF ligands, and heparin glycans or proteoglycans.Extracellular FGFR activation by FGF ligand binding to an FGFR initiatesa cascade of signaling events inside the cell, beginning with thereceptor tyrosine kinase activity.

To date, there are 23 known FGFs, each with the capacity to bind one ormore FGFRs (Zhang et al., J. Biol. Chem. 281:15, 694-15,700 (2006)).Several FGFs can bind to and activate each of one or more FGFRs, oftenwith large differences, for example, order of magnitude differences intheir affinities for the different FGFRs. Many FGFs bind theirrespective FGFRs with very high affinities, some in the picomolar range.Heparin is required for the binding of FGFs to FGFRs under somecircumstances (Ornitz et al., Mol. Cell Biol. 12:240 (1992)). Forexample, the mitogenic response to FGF-2 (also known as basic FGF(bFGF)) mediated by FGFR1 has been shown to depend on the presence ofheparin (Ornitz et al., Mol. Cell Biol. 12:240 (1992)).

Previously proposed therapeutic approaches using specific antibodies toblock FGF function do not address the issue of redundancy within the FGFfamily in activating multiple FGFRs, since cancers or otherproliferative cells may express upregulated levels of more than one FGFor FGFR. Antisense oligonucleotide or related siRNA therapies havepotential problems with specificity, serum half-life, and intracellulardelivery. Gene transfer therapies, including those using adenovirus,have raised issues of patient safety and a number of clinical genetherapy studies have been halted due to patient death. Small moleculetyrosine kinase inhibitor therapies suffer from issues of targetspecificity, toxicity, and manifestations of drug resistance. To date,no drug which targets an FGFR signaling pathway has been approved fortreating any human disease.

SUMMARY

The invention provides an FGFR fusion protein comprising a firstpolypeptide that comprises an extracellular domain of an FGFRpolypeptide and a fusion partner, wherein the extracellular domaincomprises a C-terminus, wherein the C-terminus comprises a variant of awildtype FGFR extracellular domain C-terminus, wherein the variantcomprises a deletion of 1-22 amino acid residues present in a wildtypeFGFR1, FGFR2, FGFR3, or FGFR4 extracellular domain C-terminus, andwherein the FGFR fusion protein binds at least one FGF ligand or abiologically active fragment thereof. In an embodiment, the deletion isC-terminal to a valine residue situated at the C-terminus of the IgIIIdomain and commonly aligned among the wildtype FGFR1, FGFR2, FGFR3, andFGFR4 extracellular domain C-termini. In an embodiment, the FGFR fusionprotein is less susceptible to cleavage.

The invention also provides an FGFR fusion protein comprising a firstpolypeptide that comprises an extracellular domain of an FGFRpolypeptide and a fusion partner; wherein the extracellular domaincomprises a C-terminus, wherein the C-terminus comprises a variant of awildtype FGFR extracellular domain C-terminus, wherein the variantcomprises at least one point mutation compared to a wildtype FGFR1,FGFR2, FGFR3, or FGFR4 extracellular domain C-terminus; and wherein thepoint mutation renders the FGFR fusion protein less susceptible tocleavage.

Any of these FGFR fusion proteins may comprise an FGFR1 polypeptide, anFGFR2 polypeptide, an FGFR3 polypeptide, and/or an FGFR4 polypeptide.Any of these FGFR fusion proteins may comprise an Fc polypeptide.

In an embodiment, the extracellular domain of the FGFR fusion proteincomprises an amino acid sequence of any of SEQ ID NO: 100, SEQ ID NO: 97to SEQ ID NO.: 99, SEQ ID NO.: 101 to SEQ ID NO: 122, SEQ ID NO: 127 toSEQ ID NO: 132, SEQ ID NO: 137 to SEQ ID NO: 141, SEQ ID NO: 146 to SEQID NO: 150, SEQ ID NO: 162 to SEQ ID NO: 166, SEQ. ID. NOS.:178 to SEQID NO: 182, SEQ ID NO: 199 to SEQ ID NO: 203, SEQ ID NO: 206 to SEQ IDNO: 210, SEQ ID NO: 230 to SEQ ID NO: 234, and SEQ ID NO: 238 to SEQ IDNO: 242. These FGFR fusion proteins may lack a native leader sequence.In an embodiment, the Fc polypeptide comprises an amino acid sequence ofany of SEQ ID NO: 171 to SEQ ID NO: 173.

The invention further provides an FGFR fusion protein produced in a CHOcell or a 293 cell comprising a first polypeptide comprising anextracellular domain of an FGFR polypeptide or a variant thereof and afusion partner, wherein the FGFR fusion protein can bind to one or moreFGF ligand. In an embodiment, this FGFR fusion protein comprises anamino acid sequence of any of SEQ ID NO.: 100, SEQ ID NO.: 95 to SEQ IDNO.: 99, SEQ ID NO: 102 to SEQ ID NO.: 126, SEQ ID NO: 156 to SEQ ID NO:157, SEQ ID NO: 162 to SEQ ID NO: 166, SEQ ID NO: 176 to SEQ ID NO: 182,SEQ ID NO: 198 to SEQ ID NO: 202, SEQ ID NO: 205 to SEQ ID NO: 210, SEQID NO: 228 to SEQ ID NO: 234, and SEQ ID NO: 236 to SEQ ID NO: 242. Inan embodiment, this FGFR fusion protein lacks a native leader sequence.In an embodiment, it is produced using a CHEF expression system.

The invention yet further provides the use of any of the above-describedFGFR fusion proteins as a medicament. It provides a compositioncomprising an effective amount of any of the above-described FGFR fusionproteins and a pharmaceutically acceptable carrier. The inventionprovides a kit comprising this composition in a container andinstructions for its administration into a subject in need of such acomposition. In an embodiment the kit comprises either a single dose ormultiple doses of the FGFR fusion protein.

The invention provides a nucleic acid molecule comprising apolynucleotide that encodes any of the above-described FGFR fusionproteins. In an embodiment, a vector comprises this nucleic acidmolecule and a promoter which regulates the expression of the nucleicacid molecule. The invention also provides a recombinant host cellcomprising any of the above-described FGFR fusion proteins, this nucleicacid molecule, and/or this vector. In an embodiment, this recombinanthost cell is a prokaryotic cell. In an embodiment, this recombinant hostcell is a eukaryotic cell, for example, one of CHO or 293 lineage. In anembodiment, the invention provides a polypeptide expressed from such arecombinant host cell.

In another aspect, the invention provides a method of producing an FGFRfusion protein comprising providing the recombinant host cell describedabove and culturing it to express the FGFR fusion protein. In anembodiment, the method further comprises isolating the FGFR fusionprotein from the cell culture. In an embodiment, the isolation procedurecomprises contacting the expressed FGFR fusion protein with an affinitymatrix, for example, Protein A, Protein G, Protein A/G, anti-Fcantibody, and anti-FGFR antibody. In an embodiment, the isolationfurther comprises contacting the FGFR fusion protein with a hydrophobicmatrix.

In a further aspect, the invention provides a method of detecting thelevel of FGFR expression in a subject comprising providing a ligand toFGFR, providing a tissue sample from the subject, allowing the ligandand the sample to interact under conditions that permit specific FGFRbinding, measuring the specific binding; and comparing the amount ofspecific binding to that of a control sample, wherein the ligand bindsto at least one of FGFR1, FGFR2, FGFR3, FGFR4, and a fragment of any ofthese. The tissue sample may comprise a blood, serum, or plasma sample.In an embodiment, the tissue sample comprises a sample of a diseasedtissue. In an embodiment, the tissue sample comprises a sample of atumor tissue. In an embodiment, the testing comprises a protein-antibodybinding or competition assay, or a nucleic acid hybridization assay. Inan embodiment, the ligand comprises an FGF ligand or an antibody ligand.

The invention also provides a method of detecting the level of FGFexpression in a subject comprising providing an FGFR or fragmentthereof; providing a tissue sample from the subject; allowing the ligandand the sample to interact under conditions that permit specificbinding; measuring the specific binding; and comparing the amount ofspecific binding to that of a control sample, wherein the FGFR orfragment thereof binds to the FGF. In an embodiment, the FGF is at leastone of FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9,FGF-10, FGF-16, FGF-17, FGF-18, FGF-19 and FGF-20.

The invention further provides a method of inhibiting the viability orproliferation of a proliferative cell in vitro, in vivo, or ex vivocomprising providing a composition comprising an effective amount of anFGFR fusion protein, as described above, and a pharmaceuticallyacceptable carrier, and contacting the proliferative cell with an amountof the composition effective to inhibit the viability or proliferationof the proliferative cell. In an embodiment, the proliferative cell ispresent in a subject and the subject expresses a higher level of one ormore FGF ligand than normal. In an embodiment, a tissue of this subjectexpresses a higher level of the FGF ligand than normal. In anembodiment, the FGF ligand binds to at least one of FGFR1-Fc, FGFR2-Fc,FGFR3-Fc, or FGFR4-Fc, or a variant of any of these, as determined bymeasuring binding interactions in real time. For example, this FGF maybe selected from FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-8, FGF-9,FGF-16, FGF-17, FGF-18, FGF-19 and FGF-20. In an embodiment, this methodis performed wherein the proliferative cell is present in a subject andthe subject expresses a higher level of an FGFR polypeptide than normal.In an embodiment, a tissue in the subject also expresses a higher levelof the FGFR polypeptide, for example, FGFR1, FGFR2, FGFR3, or FGFR4,than normal. In an embodiment, this method inhibits the viability and/orproliferation of a proliferative cancer cell, a proliferative dysplasticcell, or a proliferative endothelial cell. In an embodiment, theproliferative cell comprises a breast cell, a pancreatic cell, aprostate cell, a lung cell, an ovarian cell, a kidney cell, a braincell, a colorectal cell, a retinal cell, or another cell selected fromany of Table 5-Table 11. In an embodiment, the subject expresses ahigher level of an FGFR polypeptide than normal and a higher level of anFGF ligand than normal.

In yet a further aspect, the invention provides a method of treatingcancer in a subject, comprising providing any of the above-describedFGFR fusion proteins and administering an effective amount of the FGFRfusion protein to the subject. In an embodiment, the cancer comprises atleast one subpopulation of cells that is dependent on or responsive togrowth stimulation by an FGF ligand. In an embodiment, the cancercomprises at least one subpopulation of cells that is dependent on orresponsive to an angiogenic factor for production of blood vessels forgrowth. In an embodiment, the cancer is resistant to VEGF signalingpathway inhibition. In an embodiment, the cancer comprises metastasizingcancer, for example bone metastasis. In an embodiment, the cancercomprises a hematologic cancer, for example, chronic myelogenousleukemia, chronic lymphocytic leukemia, acute myelocytic leukemia, orhairy cell leukemia. In an embodiment, the cancer comprises a solidtumor. In an embodiment, the cancer comprises breast cancer, pancreaticcancer, pituitary cancer, prostate cancer, lung cancer, ovarian cancer,renal cell cancer, oral squamous cell cancer, colorectal cancer, bladdercancer, retinal cancer, brain cancer, or another cancer listed in Table5-Table 11.

In an embodiment, this method further comprises administering a secondanti-cancer therapeutic to the subject, for example, one comprising acytostatic agent, a cytotoxic agent, an anti-angiogenic agent, a secondFGFR fusion protein, an inhibitor of PDGF signaling, an inhibitor ofVEGF signaling, or an inhibitor of EGF signaling. The second anti-cancertherapeutic may be administered before, after, or contemporaneously withthe administration of the FGFR fusion protein.

The invention also provides a method of inhibiting angiogenesis in asubject comprising providing any of the above-described FGFR fusionproteins and administering an amount of the FGFR fusion protein to thesubject effective to inhibit angiogenesis. In an embodiment, this methodfurther comprises administering a second therapeutic agent to thesubject, for example, a cytostatic agent, a cytotoxic agent, a secondanti-angiogenic agent, or a second anti-angiogenic agent.

In an embodiment of this method, the subject is treated for maculardegeneration. In an embodiment, the subject is treated for cancer. In anembodiment, the second therapeutic agent comprises an anti-cancertherapeutic agent, for example, a second FGFR fusion protein, aninhibitor of PDGF signaling, an inhibitor of VEGF signaling, aninhibitor of EGF signaling, an antibody, or an siRNA. In an embodiment,the invention provides a method of treating angiogenesis in a subjectthat has been or is being treated with Avastin®.

The invention provides a method of inhibiting the viability orproliferation of a proliferative cell in vitro, in vivo, or ex vivo; amethod of treating cancer, and an method of treating angiogenesis byadministering a composition comprising an effective amount of any of theabove-described FGFR fusion proteins intravenously, intramuscularly,subcutaneously, topically, orally, intraperitoneally, intraorbitally, byimplantation, by inhalation, intrathecally, intraventricularly, and/orintranasally. In an embodiment, the method further comprisesadministering a second, anti-cancer therapeutic agent to the subject,wherein the second agent comprises surgery, chemotherapy, radiationtherapy, and/or the administration of another biologic.

The invention also provides the use of any of the above-described FGFRfusion proteins for the manufacture of a medicament for treatment of aproliferative disease, for example, cancer or macular degeneration. Inan embodiment, the cancer comprises a hematologic cancer or a solidcancer. In an embodiment, the cancer comprises breast cancer, pancreaticcancer, pituitary cancer, prostate cancer, lung cancer, ovarian cancer,renal cancer, oral cancer, colorectal cancer, bladder cancer, retinalcancer, brain cancer, or another cancer identified in Table 5-Table 11.

The invention provides a product comprising an FGFR fusion protein asdescribed above and at least one anti-cancer therapeutic as a combinedpreparation for simultaneous, separate, or sequential use to treatcancer.

BRIEF DESCRIPTION OF THE DRAWINGS AND TABLES Brief Description of theDrawings

The accompanying drawings, which are incorporated into and constitute apart of this specification, illustrate several embodiments consistentwith the invention. Together with the description, they serve to explainthe principles of the invention, but do not limit the invention.

FIG. 1A shows an amino acid sequence alignment of a portion of theextracellular and transmembrane domains of the seven FGFR isoforms,FGFR3-IIIb, FGFR3-IIIc, FGFR1-IIIb, FGFR1-IIIc, FGFR2-IIIb, FGFR2-IIIc,and FGFR4, denoting the immunoglobulin (Ig) III domain, the truncationlocations of the FGFR1 mutants R1Mut1, R1Mut2, R1Mut3, R1Mut4, andR1Mut5 variants, and the position of the Fc portion of the fusionprotein.

FIG. 1B shows the same amino acid sequence alignment as FIG. 1A,denoting the locations of the FGFR1 mutants R1Mut6, R1Mut7, R1Mut8,R1Mut9 and R1Mut10.

FIG. 2 shows the same amino acid sequence alignment as FIG. 1, denotingthe truncation locations of the FGFR4 mutants R4Mut1, R4Mut2, R4Mut3,R4Mut4, R4Mut5, and R4Mut6.

FIG. 3A shows a Western blot demonstrating that R1Mut1, R1Mut2, R1Mut3,R1Mut4, and R1Mut5 were more resistant to proteolytic cleavage by MMP-2than the parental FGFR1-IIIc-Fc.

FIG. 3B shows a quantitative Western blot demonstrating that R1Mut4 ismore resistant to MMP-2 cleavage, compared to parental FGFR1-IIIc-Fc.Quantitative standards of FGFR1-IIIc-Fc are shown on the left and cellculture medium from FGFR1-IIIc-Fc and R1Mut4 are shown on the right.

FIG. 4 shows a Western blot demonstrating that R4Mut1, R4Mut2, R4Mut3,R4Mut4, and R4Mut5 were more resistant to proteolytic cleavage by MMP-2than the full-length parental FGFR4-Fc.

FIG. 5A shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of FGFR4 mutants to FGF-1 by measuringchanges in OD₄₅₀, R4Mut1, R4Mut2, R4Mut3, R4Mut4, R4Mut5, and R4Mut6each has a higher affinity for FGF-1 than the parental FGFR4-Fc, whereashuman IgG did not bind to FGF-1.

FIG. 5B shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of FGFR4 mutants to FGF-2 by measuringchanges in OD₄₅₀, R4Mut1, R4Mut2, R4Mut3, R4Mut4, and R4Mut5 each has ahigher affinity for FGF-2 than the parental FGFR4-Fc, whereas human IgGdid not bind to FGF-2.

FIG. 5C shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of FGFR4 mutants to FGF-8b bymeasuring changes in OD₄₅₀, R4Mut1, R4Mut2, R4Mut3, R4Mut4, R4Mut5, andR4Mut6 each has a higher affinity for FGF-8b than parental FGFR4-Fc,whereas human IgG did not bind to FGF-1.

FIG. 6 shows a direct ELISA assay measuring the binding of increasingconcentrations (ug/ml) of FGFR4 mutants to FGF-2 by measuring changes inOD₄₅₀. R1Mut1, R1Mut2, R1Mut3, and R1Mut4, but not R1Mut5, were able tobind FGF-2 as well as or better than parental FGFR1-IIIc-Fc.

FIG. 7 shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of FGFR4 fusion proteins produced ineither 293-6E cells or CHO cells to FGF-2. FGFR-IIIc-Fc produced byeither 293-6E or by CHO host cells were able to bind and sequester FGF-2to approximately the same extent, whereas human IgG was not able to bindFGF-2.

FIG. 8A shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of parental FGFR-IIIc-Fc and R1Mut4,both produced by DG44 host cells, were able to bind and sequester FGF-1to approximately the same extent. Human IgG was not able to bind FGF-1.

FIG. 8B shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of parental FGFR-IIIc-Fc and R1Mut4,both produced by DG44 host cells, were able to bind and sequester FGF-2to approximately the same extent. Human IgG was not able to bind FGF-2.

FIG. 9 shows a competition ELISA assay measuring the binding ofincreasing concentrations (ug/ml) of parental FGFR-IIIc-Fc and R1Mut4,both produced by DG44 host cells, were able to bind and sequester FGF-8bto approximately the same extent. Human IgG was not able to bind FGF-8b.

FIG. 10 shows a competition ELISA assay measuring the ability ofincreasing concentrations (ug/ml) of parental FGFR1-IIIc-Fc,FGFR3-IIIc-Fc, and FGFR4-Fc to inhibit FGF-1 binding to FGFR1-IIIc-Fc.

FIG. 11 shows a competition ELISA assay, as described in FIG. 10,measuring the ability of parental FGFR1-IIIc-Fc, FGFR3-IIIc-Fc, andFGFR4-Fc to inhibit FGF-2 binding to FGFR1-IIIc-Fc.

FIG. 12 shows a competition ELISA assay, as described in FIG. 11,measuring the ability of FGFR1-IIIc-Fc, FGFR3-IIIc-Fc, and FGFR4-Fc toinhibit FGF-8 binding to FGFR1-IIIc-Fc.

FIG. 13 shows a competition phospho-Erk ELISA assay, measuring changesin OD₄₅₀ induced by increasing concentrations (ug/ml) of parentalFGFR1-IIIc-Fc made by 293 cells or by CHO cells. Both parentalconstructs inhibited FGF-2 activated Erk phosphorylation, while humanIgG was unable to do so.

FIG. 14 shows a competition phospho-Erk ELISA assay, measuring changesin OD₄₅₀ induced by increasing concentrations (ug/ml) of parentalFGFR1-IIIc-Fc, R1Mut4, and R1Mut5. Parental FGFR1-IIIc-Fc and R1Mut4,but not R1Mut5 or human IgG, inhibited FGF-2 activated Erkphosphorylation.

FIG. 15 shows a CellTiterGlo™ viability assay demonstrating thedose-dependent inhibitory effect of FGFR1-IIIc-Fc at concentrations of20 ug/ml, 4.0 ug/ml, and 0.8 ug/ml on the viability and proliferation ofU251 malignant glioblastoma cells plated at a concentration of 1000cells per well in 10% FCS. Human IgG had no effect. The positivecontrol, TRAIL, induced maximum inhibition.

FIG. 16 shows a CellTiterGlo™ viability assay demonstrating thedose-dependent inhibitory effect of FGFR1-IIIc-Fc at concentrations of20 ug/ml, 4.0 ug/ml, and 0.8 ug/ml on the viability and proliferation ofU251 malignant glioblastoma cells plated at a concentration of 5000cells per well in 1.0% FCS. Human IgG had no effect. The positivecontrol, TRAIL, induced maximum inhibition.

FIG. 17 shows a CellTiterGlo™ viability assay demonstrating thedose-dependent inhibitory effect of FGFR1-IIIc-Fc at concentrations of20 ug/ml, 4.0 ug/ml, and 0.8 ug/ml on the viability and proliferation ofU251 malignant glioblastoma cells plated at a concentration of 10,000cells per well in 0.1% FCS. Human IgG had no effect. The positivecontrol, TRAIL, induced maximum inhibition.

FIG. 18 lists cancer cell lines which were tested for their sensitivityto inhibition of their viability and proliferation by FGFR1-IIIc-Fc.Their malignancy origins and their sensitivity to FGFR1-IIIc-Fc isshown.

FIG. 19 shows a CellTiterGlo™ viability assay demonstrating thedose-dependent inhibitory effect of both FGFR1-IIIc-Fc and FGFR4-Fc onthe viability and proliferation of A549 lung carcinoma cells.

FIGS. 20A-G compare the inhibitory effect of FGFR1-IIIb-Fc,FGFR1-IIIc-Fc, FGFR2-IIIb-Fc, FGFR2-IIIc-Fc, FGFR3-IIIb-Fc,FGFR3-IIIc-Fc, and FGFR4-Fc on the viability and proliferation of tumorcells from tumor cell lines, showing increasing inhibition (%inhibition) with increased concentration of the fusion proteins(treatment protein (ug/ml)). Data is shown for A549 cells (FIG. 20A),U118 cells (FIG. 20B), U251 cells (FIG. 20C), SF268 cells (FIG. 20D),T47D cells (FIG. 20E), and Caki-1 cells (FIG. 20F). FIG. 20G shows theconcentration-dependent inhibitory effect of parental FGFR1-IIIc andR1Mut4, but not R1Mut5, on the viability and proliferation of A549 cellsand U251 cells.

FIG. 21 summarizes the results shown in FIG. 20 by listing the percentinhibition of the viability and proliferation of A549, U118, U251,SF268, T47D, and Caki-1 tumor cells induced by FGFR1-IIIb-Fc,FGFR1-IIIc-Fc, FGFR2-IIIb-Fc, FGFR2-IIIc-Fc, FGFR3-IIIb-Fc,FGFR3-IIIc-Fc, and FGFR4-Fc, respectively.

FIG. 22 shows the concentration of FGFR1-IIIc-Fc (ug/ml) in the sera ofthree mice injected with “mini-circle” vector cDNA encodingFGFR1-IIIc-Fc using the hydrodynamic tail vein injection method, asmeasured by direct ELISA assay and monitored for about 45 days postinjection.

FIG. 23 shows the presence of functional, circulating FGFR1-IIIc-Fc insera of mice injected with “mini-circle” vector cDNA encodingFGFR1-IIIc-Fc using the hydrodynamic tail vein injection method,compared to sera from control mice, as measured by a quantitativecompetition ELISA assay.

FIG. 24 shows of the serum concentration of functional, circulatingR1Mut4 in the sera of each of four mice by mice injected with“mini-circle” vector cDNA encoding R1Mut4 using the hydrodynamic tailvein injection method, measured by a quantitative competition ELISAassay on days 2 and 7 post-injection.

FIG. 25 shows the inhibitory effect of FGFR1-IIIc-Fc on Caki-1 tumorgrowth in an in vivo xenograft mouse model of tumor growth in which micewere injected with “mini-circle” vector cDNA encoding FGFR1-IIIc-Fcusing the hydrodynamic tail vein injection method. The tumor volumeincreased more slowly in the animals treated with FGFR1-IIIc-Fc thanwith saline.

FIG. 26 shows a Western blot of sera taken from mice 5 min, 30 min, 24hr, 48 hr, and 72 hr after injection with purified FGFR1-IIIc-Fcproduced from 293 cells or from CHO cells, compared to control mouseserum. The blot shows immunoreactivity with anti-human Fc antibody anddemonstrates that FGFR1-IIIc-Fc from CHO cells persisted in thecirculation longer (more than 72 hours after injection) and thus wasmore stable in vivo than FGFR1-IIIc-Fc from 293-6E cells, which wasundetectable after 24 hours.

FIG. 27 shows a chromatographic analysis of the N-labeled glycans ofFGFR1-IIIc-Fc expressed from 293-6E cells (upper panel) and CHO cells(lower panel).

FIG. 28 shows the amount of FGFR1-IIIc-Fc in mouse serum measured for 25days following injection of FGFR1-IIIc-Fc protein, as detected byquantitative direct ELISA.

FIG. 29 shows the amount of functional FGFR1-IIIc-Fc present in the seraof mice 30 min, 5 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 7 days,14 days, and 25 days following injection with FGFR1-IIIc-Fc protein, asmeasured by a quantitative FGF-2 competition ELISA assay. The decreasein functional FGFR1-IIIc-Fc is measured as a decrease in OD₄₅₀ resultingfrom an increasing volume of serum (ul). Functional FGFR1-IIIc-Fcremains in mouse serum more than 14 days following injection withFGFR1-IIIc-Fc.

FIG. 30A shows the inhibitory effect of three concentrations ofFGFR1-IIIc-Fc on Caki-1 tumor growth in an in vivo xenograft mouse modelof tumor growth in which mice were injected intravenously withFGFR1-IIIc-Fc fusion protein.

FIG. 30B shows the concentration-dependent inhibitory effect ofFGFR1-IIIc-Fc and the inhibitory effect of R1Mut4 on Caki-1 tumorgrowth, as described in FIG. 30A.

FIG. 31 shows a quantitative Western blot of sera from mice injectedwith either FGFR1-IIIc-Fc or R1Mut4 proteins at 4 hr, 3 days, and 7 daysafter injection, blotted with an anti-human Fc antibody, and compared toa set of FGFR1-IIIc-Fc standards. FGFR1-IIIc-Fc and R1Mut4 were bothstable in vivo in mice up to at least about 7 days following injectionwith “mini-circle” vector cDNA encoding FGFR1-IIIc-Fc or R1Mut4 byhydrodynamic tail vein injection.

FIG. 32 shows the real-time ligand binding profiles of FGFR1-IIIc-Fc andR1Mut4 to FGF-1, FGF-2, FGF-4, and FGF-5, measured by surface plasmonresonance.

DEFINITIONS

The terms used herein have their ordinary meanings, and, morespecifically, as set forth below, and as can be further understood inthe context of the specification.

The terms “nucleic acid molecule” and “polynucleotide” may be usedinterchangeably to refer to a polymer of nucleotides, such as DNA; RNA;RNAi; siRNA, whether genomic or cDNA or cRNA or anti-sense RNA; and maycontain natural or non-natural nucleic acids or polynucleotides oractive fragments thereof.

The terms “polypeptide” and “protein” are used interchangeably to referto a polymer of amino acid residues, comprising natural or non-naturalamino acid residues, and are not limited to a minimum length. Thus,peptides, oligopeptides, dimers, multimers, and the like are includedwithin the definition. Both full-length proteins and fragments thereofare encompassed by the definition. The terms also includepost-translational modifications of the polypeptide, including, forexample, glycosylation, sialylation, acetylation, and phosphorylation.Furthermore, a “polypeptide” herein also refers to a modified proteinsuch as single or multiple amino acid residue deletions, additions, andsubstitutions to the native sequence, as long as the protein maintains adesired activity. For example, a serine residue may be substituted toeliminate a single reactive cysteine or to remove disulfide bonding or aconservative amino acid substitution may be made to eliminate a cleavagesite. These modifications may be deliberate, as through site-directedmutagenesis, or may be accidental, such as through mutations of hostswhich produce the proteins or errors due to polymerase chain reaction(PCR) amplification.

An “extracellular domain” (“ECD”) is the portion of a polypeptide thatextends beyond the transmembrane domain into the extracellular space.The term “extracellular domain,” as used herein, may comprise a completeextracellular domain or may comprise a truncated extracellular domainmissing one or more amino acids. The extracellular domains of FGFRs(defined below) bind to one or more FGFs. The composition of theextracellular domain may depend on the algorithm used to determine whichamino acids are in the membrane. Different algorithms may predict, anddifferent systems may express, different extracellular domains for agiven FGFR. For example, a tyrosine (Y) residue may be considered as thefirst amino acid residue in the transmembrane domain or the last aminoacid residue of the extracellular domain, depending on the method usedto determine the extracellular domain.

A “fibroblast growth factor receptor” (FGFR) polypeptide, as usedherein, is a polypeptide comprising the entirety or a portion of FGFR1,FGFR2, FGFR3, or FGFR4 including all its naturally occurring isoforms orallelic variants. An “FGFR1 polypeptide,” for example, refers to apolypeptide having the amino acid sequence of any one of the known FGFR1polypeptides, such as FGFR1-IIIb and FGFR1-IIIc, and any fragmentthereof, including those described in U.S. Pat. Nos. 6,656,728;6,384,191; 5,229,501; 6,255,454; 6,344,546; 5,474,914; and 5,288,855.FGFR1-IIIb and FGFR1-IIIc differ from each other in their IgIII domains(defined below). An FGFR2 polypeptide, for example, refers to apolypeptide having the amino acid sequence of any one of the known FGFR2polypeptides, for example, FGFR2-IIIb and FGFR2-IIIc, and any fragmentsthereof. FGFR2-IIIb and FGFR2-IIIc differ from each other also in theIgIII domains. An “FGFR3 polypeptide,” for example, refers to apolypeptide having the amino acid sequence of any one of the known FGFR3polypeptides, for example, FGFR3-IIIb and FGFR3-IIIc and any fragmentsthereof. FGFR3-IIIb and FGFR3-IIIc also differ from each other in theirIgIII domains. An “FGFR4 polypeptide,” for example, refers to apolypeptide having the amino acid sequence of any one of the known FGFR4polypeptides, and any fragments thereof.

An “FGFR fusion protein” is a protein as defined in the Tables andSequence Listing and typically comprises a sequence of amino acidscorresponding to the extracellular domain of an FGFR polypeptide or abiologically active fragment thereof, and a fusion partner. The fusionpartner may be joined to either the N-terminus or the C-terminus of theFGFR polypeptide and the FGFR may be joined to either the N-terminus orthe C-terminus of the fusion partner. An FGFR fusion protein can be aproduct resulting from splicing strands of recombinant DNA andexpressing the hybrid gene. It can be made by genetic engineering, forexample, by removing the stop codon from the DNA sequence of the firstprotein, then appending the DNA sequence of the second protein in frame,so that the DNA sequence is expressed as a single protein. Typically,this is accomplished by cloning a cDNA into an expression vector inframe with an existing gene. An FGFR fusion protein may comprise afusion partner comprising amino acid residues that represent all of, ormore than one fragment of, more than one gene. An FGFR fusion proteinmay also comprise a fusion partner which is not a polypeptide, but whichis chemically attached.

The “valine residue that is situated at the C-terminus of the IgIIIdomain and commonly aligned among the wildtype FGFR1, FGFR2, FGFR3, andFGFR4 ECD C-termini” is the valine (V) residue shown in bold below.

R1-IIIb 348 ANQSAWLTVTRPVAKALEERPAVMTSPLYLE R1-IIIc 348SHHSAWLTVL----EALEERPAVMTSPLYLE R2-IIIb 349ANQSAWLTVLPK-QQAPGREKEITASPDYLE R2-IIIC 351SFHSAWLTVLP----APGREKEITASPDYLE R3-IIIb 347AEKAFWLSVHGPRAAEEELVEADEAGSVYAG R3-IIIc 348SHHSAWLVVLP---AEEELVEADEAGSVYAG R4 342 SYQSAWLTVLP---EEDPTWTAAAPEARYTD

A “fusion partner” is any component of a fusion molecule in addition tothe extracellular domain of an FGFR or fragment thereof. A fusionpartner may comprise a polypeptide, such as a fragment of animmunoglobulin molecule, or a non-polypeptide moiety, for example,polyethylene glycol. The fusion partner may comprise an oligomerizationdomain such as an Fc domain of a heavy chain immunoglobulin.

An “FGF ligand” is a fibroblast growth factor, or variant or fragmentthereof, which binds to an FGFR. Currently, the known FGF ligandsinclude FGF-1, FGF-2, FGF-3, FGF-4, FGF-5, FGF-6, FGF-7, FGF-8, FGF-9,FGF-10, FGF-11, FGF-12, FGF-13, FGF-14, FGF-15, FGF-16, FGF-17, FGF-18,FGF-19, FGF-20, FGF-21, FGF-22, and FGF-23. Each FGF may bind to one ormore FGFR. An FGF ligand is “over-expressed” when it is expressed at ahigher level than normal for the cell, tissue, or organism expressingthe ligand.

A “fragment crystallizable (Fc) polypeptide” is the portion of anantibody molecule that interacts with effector molecules and cells. Itcomprises the C-terminal portions of the immunoglobulin heavy chains. Asused herein, an Fc polypeptide comprises a fragment of the Fc domainwith one or more biological activity of an entire Fc polypeptide. An“effector function” of the Fc polypeptide is an action or activityperformed in whole or in part by an antibody in response to a stimulusand may include complement fixation or ADCC (antibody-dependent cellularcytotoxicity) induction.

“Wildtype” refers to a non-mutated version of a gene, allele, genotype,polypeptide, or phenotype, or a fragment of any of these. It may occurin nature or be produced recombinantly. A “wildtype FGFR ECD” refers toa protein or a nucleic acid molecule that contains an amino acidsequence or nucleic acid sequence that is identical to that of awildtype extracellular domain of an FGFR, in whole or in part, includingall isoforms of FGFR1, FGFR2, FGFR3, and FGFR4.

A “variant” is a nucleic acid molecule or polypeptide that differs froma referent nucleic acid molecule or polypeptide by single or multipleamino acid substitutions, deletions, and/or additions and substantiallyretains at least one biological activity of the referent nucleic acidmolecule or polypeptide.

A “point mutation” is a mutation that involves a single nucleotide oramino acid residue. The mutation may be the loss of a nucleotide oramino acid, substitution of one nucleotide or amino acid residue foranother, or the insertion of an additional nucleotide or amino acidresidue.

“Leader sequence” refers to a sequence of amino acid residues orpolynucleotides encoding such, which facilitates secretion of apolypeptide of interest and is typically cleaved upon export of thepolypeptide to the outside of the cell surface membrane.

A “vector” is a plasmid that can be used to transfer DNA sequences fromone organism to another or to express a gene of interest. A vectortypically includes an origin of replication and regulatory sequenceswhich regulate the expression of the gene of interest, and may or maynot carry a selective marker gene, such as an antibiotic resistancegene. A vector is suitable for the host cell in which it is to beexpressed. A vector may be termed a “recombinant vector” when the geneof interest is present in the vector.

A “host cell” is an individual cell or cell culture which can be or hasbeen a recipient of any recombinant vector or isolated polynucleotide.Host cells include the progeny of a single host cell, which may notnecessarily be completely identical, for example, in morphology or intotal DNA complement, to the original parent cell due to natural,accidental, or deliberate mutation and/or change. A host cell includes acell transfected or infected in vivo or in vitro with a recombinantvector or a polynucleotide of the invention. A host cell which comprisesa recombinant molecule may be called a “recombinant host cell.” Hostcells may be prokaryotic cells or eukaryotic cells. Eukaryotic cellssuitable for use as host cells include mammalian cells, such as primateor non-primate animal cells; fungal cells; plant cells; and insectcells. For example, host cells may be derived from 293 or CHO cells.

A “promoter” is a DNA regulatory region capable of binding RNApolymerase in a cell and initiating transcription of a downstream (5′ to3′ direction) coding sequence operably linked thereto. Promoters includethose that are naturally contiguous to a nucleic acid molecule and thosethat are not naturally contiguous to a nucleic acid molecule.Additionally, the term “promoter” includes inducible promoters,conditionally active promoters such as a cre-lox promoter, tet induciblepromoters, constitutive promoters, and tissue specific promoters. An“exogenous promoter” is one that is not operatively linked to a gene ofinterest in the naturally-occurring state.

“CHEF expression system” refers to an expression system utilizingregulatory DNA sequences derived from the hamster elongation factor-1(EF-1) alpha gene, as described in U.S. Pat. No. 5,888,809 as theregulatory sequences. CHEF expression systems may use Chinese hamsterovary (CHO) cells as host cells.

The CHEF expression system comprises regulatory DNA sequences 5′ totranslated regions of the Chinese hamster ovary EF-1alpha gene andincludes approximately 3.7 kb DNA extending from a Spe1 restriction siteto the initiating methionine (ATG) codon of the EF-1alpha protein.Polynucleotides of less than 3.7 kb are also included in as much as thesmaller fragment polynucleotides are capable of increasing transcriptionof an operatively linked gene. Examples of plasmids containing thisregulatory system include pDEF2 and pDEF10. Plasmid pDEF2 in E. colistrain XL-1 Blue was deposited with from American Type TissueCollection, 10801 University Boulevard, Manassas, Va. 20110 and assignedAccession Number 98343.

“Isolating” a protein from cell culture means separating the proteinfrom the remainder of the materials in the cell culture. “Isolating” canmean achieving a partial or a complete separation of the protein fromthe culture. “Isolating” and “purifying” are used interchangeably, asare “isolated” and “purified.”

An “affinity matrix” refers to a composition that shows preferentialaffinity to a polypeptide or polynucleotide of interest and is used forpurification or isolation of such from other materials naturally presentin its environment, for example, in a cell culture. Materials suitablefor use as an affinity matrix include, but are not limited to, ProteinA, Protein G, a combination of Protein A and G, and an antibody, such asthat attached to a solid substrate.

A “biologically active” entity, or an entity having “biologicalactivity,” is an entity having any function related to or associatedwith a metabolic or physiological process, and/or having structural,regulatory, or biochemical functions of a naturally-occurring molecule.Biologically active polynucleotide fragments are those exhibitingactivity similar, but not necessarily identical, to an activity of apolynucleotide of the present invention. A biologically activepolypeptide or fragment thereof includes one that can participate in abiological reaction, including, but not limited to, a ligand-receptorinteraction or antigen-antibody binding. The biological activity caninclude an improved desired activity, or a decreased undesirableactivity. An entity may demonstrate biological activity when itparticipates in a molecular interaction with another molecule, such ashybridization, when it has therapeutic value in alleviating a diseasecondition, when it has prophylactic value in inducing an immuneresponse, when it has diagnostic and/or prognostic value in determiningthe presence of a molecule, such as a biologically active fragment of apolynucleotide that may be detected as unique for the polynucleotidemolecule, and when it can be used as a primer in a polymerase chainreaction (PCR).

“Subject,” “individual,” “host,” “animal,” and “patient” are usedinterchangeably herein to refer to mammals, including, but not limitedto, rodents, simians, humans, felines, canines, equines, bovines,porcines, ovines, caprines, mammalian laboratory animals, mammalian farmanimals, mammalian sport animals, and mammalian pets.

A “tissue sample” is any biological specimen derived from a patient. Theterm includes, but is not limited to, biological fluids such as blood,serum, plasma, urine, cerebrospinal fluid, tears, saliva, lymph,dialysis fluid, lavage fluid, semen, and other liquid samples, as wellas cell and tissues of biological origin. The term also includes cellsor cells derived therefrom and the progeny thereof, including cells inculture, cell supernatants, and cell lysates. It further includes organor tissue culture-derived fluids, tissue biopsy samples, tumor biopsysamples, stool samples, and fluids extracted from physiological tissues,as well as cells dissociated from solid tissues, tissue sections, andcell lysates. This definition encompasses samples that have beenmanipulated in any way after their procurement, such as by treatmentwith reagents, solubilization, or enrichment for certain components,such as polynucleotides or polypeptides. Also included in the term arederivatives and fractions of patient samples. A patient sample may beused in a diagnostic, prognostic, or other monitoring assay.

A “growth factor receptor signaling inhibitor,” such as a “PDGFsignaling inhibitor,” a “VEGF signaling inhibitor,” or an “EGF signalinginhibitor” is an agent that diminishes the effects of one or more of aseries of events, such as in a signaling transduction pathway, beginningwith the binding of the growth factor to its receptor and ending with abiological response, such as a proliferative response. A growth factorreceptor signaling inhibitor may diminish one or more of many events,occurring both in series and in parallel, including signal transduction,kinase activation, gene activation, and cell cycle modulation.

The terms “antibody” and “immunoglobulin” refer to a protein, generatedby the immune system, made synthetically, or made recombinantly, that iscapable of recognizing and binding to a specific antigen; antibodies arecommonly known in the art. They can be polyclonal antibodies, monoclonalantibodies, single chain antibodies or antigen binding fragmentsthereof.

“Angiogenesis” is the development of new blood vessels, includingcapillary vessels. It can take place in health or disease, includingcancer. The term includes neovascularization, revascularization,angiopoiesis, and vasculogenesis. New blood vessel growth typicallyresults from stimulation of endothelial cells by angiogenic factorswhich may be active in proliferative conditions, such as in cancer ormacular degeneration. An “angiogenic factor” is one that promotesangiogenesis.

“Cancer” and “tumor” are interchangeable terms that refer to anyabnormal cell or tissue growth or proliferation in an animal. As usedherein, the terms “cancer” and “tumor” encompass solid andhematological/lymphatic cancers and also encompass malignant,pre-malignant, and benign growth, such as dysplasia.

“Metastasis” is the spread or dissemination of a disease-process, forexample cancer, from one part of the body to another. It includes thespread or dissemination from an initial or primary site of disease toanother site. “Metastasis” also refers to the process by which suchspreading or dissemination occurs. The term is not limited to themechanism of spread or dissemination. “Metastasis” includes the spreador dissemination of cancer cells by the lymphatics or blood vessels orby direct extension through serous cavities or subarachnoid or otherspaces.

“Macular degeneration” is any condition in which the cells of the maculalutea degenerate, eventually resulting in blurred vision and possibly inblindness.

“Treatment,” as used herein, covers any administration or application ofa therapeutic for disease in a mammal, including a human, and includesinhibiting the disease, arresting its development, or relieving thedisease, for example, by causing regression, or restoring or repairing alost, missing, or defective function; or stimulating an inefficientprocess. Treatment may achieved with surgery, radiation, chemotherapy,and/or with a biologic.

A “pharmaceutically acceptable carrier” refers to a non-toxic solid,semisolid, or liquid filler, diluent, encapsulating material,formulation auxiliary, or carrier conventional in the art for use with atherapeutic agent for administration to a subject. A pharmaceuticallyacceptable carrier is non-toxic to recipients at the dosages andconcentrations employed and is compatible with other ingredients of theformulation. The pharmaceutically acceptable carrier is appropriate forthe formulation employed. For example, if the therapeutic agent is to beadministered orally, the carrier may be a gel capsule. If thetherapeutic agent is to be administered subcutaneously, the carrierideally is not irritable to the skin and does not cause injection sitereaction.

A “biologic” is a product which is naturally produced in some form byliving organisms, whether modified or unmodified, whether in whole or afragment thereof. A biologic may be prepared from a living source, suchas animal tissue. The term includes, but is not limited to, apolynucleotide, polypeptide, antibody, cell, virus, toxin, vaccine,blood component or derivative, and fusion protein. A “biologic” may beused to treat an animal, including a human.

“Surface plasmon resonance” is a reduction in reflected light intensitywhich occurs when light is reflected off a thin metal film and afraction of the incident light energy can interact with delocalisedelectrons in the metal film (plasmon).

FGFR Extracellular Domain Fusion Molecules

The FGFR fusion molecules of the invention comprise a first polypeptidethat comprises an extracellular domain (ECD) of an FGFR polypeptide anda fusion partner. The FGFR polypeptide can be any of FGFR1, FGFR2,FGFR3, and FGFR4, including all their variants and isoforms. Hence, thefamily of FGFR polypeptides suitable for use in the invention includesFGFR1-IIIb, FGFR1-IIIc, FGFR2-IIIb, FGFR2-IIIc, FGFR3-IIIb, FGFR3-IIIc,and FGFR4, for example. The extracellular domain of the FGFR can be theentire ECD or a portion thereof. The FGFR ECD is modified, as comparedto the wildtype FGFR ECD, and possesses ligand binding activity. Themodifications may be single or multiple amino acid deletions, additions,or substitutions. FGFR extracellular domains can be attached to fusionpartners that provide desired pharmacokinetic properties, for example,increasing their half-life in vivo. The fusion partner of the FGFRfusion molecules of the invention can be any fusion partner conventionalin the art, including those having oligomerization domains, such asdimerization domains, for example, an Fc fragment. Fusion partners ofthe invention also include those made by chemical modifications, such aspegylation.

FGFRs bind their cognate FGFs via their extracellular domains, thus theextracellular domain determines the ligand binding specificity. The FGFRextracellular domain can comprise up to three immunoglobulin-like(Ig-like) domains, IgI, IgII, and IgIII domains. Alternative mRNAsplicing produces several forms of the extracellular domains. Onesplicing event eliminates the amino-terminal Ig-like domain (domain I)resulting in a short form of the receptor with only two Ig-like domains.Another mRNA splicing event takes place in FGFR1, FGFR2, and FGFR3,which results in three alternative versions of Ig-like domain III;namely, IIIa, IIIb, and IIIc. So far, FGFR4 has not been reported to bealternatively spliced in this region. The third immunoglobulin-likedomain can produce receptor splice variants with different ligandbinding properties.

The invention provides compositions comprising and methods of using suchFGFR fusion molecules. FGFR fusion molecules of the invention caninclude the ECDs of FGFR1, for example those described in U.S. Pat. Nos.6,384,191; 6,656,728; 5,229,501; 6,344,546; and 5,474,914; includingthose annotated as NP_075594, NP_056934, or NP_000595, as described bythe National Center for Bioinformatics Information (NCBI). FGFR fusionmolecules of the invention can also include the ECDs of FGFR2, forexample those annotated as Ser. No. 15/281,415 and NP_000132. FGFRfusion molecules of the invention can further include the ECDs of FGFR3,for example, those annotated as NP_056934, 17939658, P22607, NP_000133,or NP_075254. FGFR fusion molecules of the invention can yet furtherinclude the ECDs of FGFR4, for example those annotated NP_002002,13991618, 2832350, 31372, and 182571.

The fusion proteins of the invention can comprise an entire ECD or aportion of the ECD of wildtype or variant FGFRs. For example, the fusionproteins of the invention can comprise the entire FGFR1 ECD, includingthat of wildtype FGFR1-IIIb or wildtype FGFR1-IIIc ECD. The inventioncan also comprise a variant of the wildtype FGFR1 ECD, such as onehaving deletion of one or more and up to 22 amino acid residues,counting from the C-terminus of the wildtype FGFR1 ECD, provided thatthe variant ECD retains at least one of its FGF ligand bindingactivities. In an embodiment, the FGFR1 ECD has the 22 amino acids atthe C-terminus deleted. In an embodiment, the deletion does not extendto or include the valine residue at amino acid residue 356 of thewildtype full length FGFR1-IIIb or FGFR1-IIIc. Examples of such variantsinclude those having amino acid residues LYLE deleted (SEQ ID NO: 243),those having amino acid residues PLYLE (SEQ ID NO: 244) deleted, thosehaving amino acid residues MTSPLYLE deleted (SEQ ID NO: 245), thosehaving amino acid residues AVMTSPLYLE deleted (SEQ ID NO: 246), thosehaving amino acid residues VMTSPLYLE (SEQ ID NO: 247) deleted, thosehaving amino acid residues EERPAVMTSPLYLE deleted (SEQ ID NO: 248),those having amino acid residues LEERPAVMTSPLYLE deleted (SEQ ID NO:249), those having amino acid residues KALEERPAVMTSPLYLE deleted (SEQ IDNO: 250), those having amino acid residues EALEERPAVMTSPLYLE deleted(SEQ ID NO: 251), and those having amino acid residuesRPVAKALEERPAVMTSPLYLE deleted (SEQ ID NO: 252), all as compared towildtype FGFR1-IIIb or FGFR1-IIIc.

In an embodiment, the fusion proteins of the invention can comprise anentire FGFR2 ECD, including that of wildtype FGFR2-IIIb or wildtypeFGFR2-IIIc ECD. The invention can also comprise a variant of thewildtype FGFR2 ECD, such as one having deletion of one or more and up to22 amino acid residues, counting from the C-terminus of the wildtypeFGFR2 ECD, provided that the variant ECD retains at least one of its FGFligand binding activities. In an embodiment, the FGFR2 ECD has the 22amino acids at the C-terminus deleted. In an embodiment, the deletiondoes not extend to or include the valine residue at amino acid residue357 of the wildtype full length FGFR2-IIIb or amino acid residue 359 ofthe wildtype full length FGFR2-IIIc. Examples of such variants includethose having amino acid residues DYLE deleted (SEQ ID NO: 253), thosehaving amino acid residues PDYLE deleted (SEQ ID NO: 254), those havingamino acid residues TASPDYLE deleted (SEQ ID NO: 255), those havingamino acid residues ITASPDYLE deleted (SEQ ID NO: 256), those havingamino acid residues EITASPDYLE deleted (SEQ ID NO: 257), those havingamino acid residues GREKEI TASPDYLE deleted (SEQ ID NO: 258), thosehaving amino acid residues PGREKEIT ASPDYLE deleted (SEQ ID NO: 259),those having amino acid residues APGREKEIT ASPDYLE deleted (SEQ ID NO:260), those having amino acid residues PAPGREKE ITASPDYLE deleted (SEQID NO: 261), those having amino acid residues QAPGRE KEITASPDYLE deleted(SEQ ID NO: 262), and those having amino acid residuesPKQQAPGREKEITASPDYLE deleted (SEQ ID NO: 263), all as compared towildtype FGFR2-IIIb or FGFR2-IIIc.

In an embodiment, the fusion proteins of the invention can comprise anentire FGFR3 ECD, including that of wildtype FGFR3-IIIb or wildtypeFGFR3-IIIc ECD. The invention can also comprise a variant of thewildtype FGFR3 ECD, such as one having deletion of one or more and up to22 amino acid residues, counting from the C-terminus of the wildtypeFGFR3 ECD, provided that the variant ECD retains at least one of its FGFligand binding activities. In an embodiment, the FGFR3 ECD has the 22amino acids at the C-terminus deleted. In an embodiment, the deletiondoes not extend to or include the valine residue at amino acid residue355 of the wildtype full length FGFR3-IIIb or amino acid residue 356 ofthe wildtype full length FGFR3-IIIc. Examples of such variants includethose having amino acid residues VYAG deleted (SEQ ID NO: 264), thosehaving amino acid residues SVYAG deleted (SEQ ID NO: 265), those havingamino acid residues EAGSVYAG deleted (SEQ ID NO: 266), those havingamino acid residues DEAGSVYAG deleted (SEQ ID NO: 267), those havingamino acid residues ADEAGSVYAG deleted (SEQ ID NO: 268), those havingamino acid residues ELVEADEAGSVYAG deleted (SEQ ID NO: 269), thosehaving amino acid residues EELVEADEAGSVYAG deleted (SEQ ID NO: 270),those having amino acid residues AEEELVEADEAGSVYAG deleted (SEQ ID NO:271), those having amino acid residues PAEEELVEADEAGSVYAG deleted (SEQID NO: 272), and those having amino acid residues GPRAAEEE LVEADEAGSVYAGdeleted (SEQ ID NO: 273), all as compared to wildtype FGFR3-IIIb orFGFR3-IIIc.

In an embodiment, the fusion proteins of the invention can comprise anentire FGFR3 ECD, including that of wildtype FGFR4 ECD. The inventioncan also comprise a variant of the wildtype FGFR4 ECD, such as onehaving deletion of one or more and up to 22 amino acid residues,counting from the C-terminus of the wildtype FGFR4 ECD, provided thatthe variant ECD retains at least one of its FGF ligand bindingactivities. In an embodiment, the FGFR4 ECD has the 22 amino acids atthe C-terminus deleted. In an embodiment, the deletion does not extendto or include the valine residue at amino acid residue 351 of thewildtype full length FGFR4. Examples of such variants include thosehaving amino acid residues RYTD deleted (SEQ ID NO: 274), those havingamino acid residues ARYTD deleted (SEQ ID NO: 275), those having aminoacid residues APEARYTD deleted (SEQ ID NO: 276), those having amino acidresidues AAPEARYTD deleted (SEQ ID NO: 277), those having amino acidresidues AAAPEARYTD deleted (SEQ ID NO: 278), those having amino acidresidues PTWTAAAPEARYTD deleted (SEQ ID NO: 279), those having aminoacid residues DPTWTAAAPEARYTD deleted (SEQ ID NO: 280), those havingamino acid residues EEDPTWTAAAPE ARYTD deleted (SEQ ID NO: 281), andthose having amino acid residues PEEDPTWTAAAPEARYTD deleted (SEQ ID NO:282), all as compared to wildtype FGFR4.

In an embodiment, the fusion proteins of the invention can comprisevariants that are point mutants, provided that they retain at least oneFGF ligand binding activity. The point mutants can include any one ormore of the amino acid residue additions, deletions, or substitutions inthe same regions of the C-terminus mentioned previously, that is, up tothe valine residue at position 356 of FGFR1-IIIb or FGFR1-IIIc; position357 of FGFR2-IIIb; position 359 of FGFR2-IIIc; position 355 ofFGFR3-IIIb; position 356 of FGFR3-IIIc; and position 350 of FGFR4. Forexample, any one or more of the amino acid residues PAVM at positions364-367 of the full length FGFR1-IIIb or FGFR1-IIIc may be added,deleted, or substituted.

The C-terminus of the extracellular and transmembrane domains of theFGFR polypeptides may differ, depending on the method used to identifythe extracellular domain. Different algorithms predict different startresidues for the transmembrane domain, thus different end residues forthe extracellular domain. For example, the extracellular domain ofFGFR1-IIIc, is shown in the sequence listing (SEQ ID NO: 92) as endingwith the amino acid sequence “YLE.” Table 2 indicates that thetransmembrane regions of FGFR1-IIIc NP_056934, NP_075594, and NP_000595begin with amino acid residues 373, which corresponds to the “L” in the“YLE” sequence. Thus, the “LE” residues may be considered as belongingeither to the extracellular domain or the transmembrane domain ofFGFR1-IIIc depending on the algorithm used for the prediction. Thisconcept applies to all of the FGFRs described herein. Thus, with respectto FIG. 1, the extracellular domain of FGFR3-IIIb may end in “VYAG” or“VY,” the ECD of FGFR3-IIIc may end in “VYAG” or “VY,” the ECD ofFGFR1-IIIb may end in “LYLE” or “LE,” the ECD of FGFR1-IIIc may end in“LYLE” or “LY,” the ECD of FGFR2-IIIb may end in “DYLE” or “DY,” the ECDof FGFR2-IIIc may end in “DYLE” or “DY,” and the ECD of FGFR4 may end in“RYTD” or “RY.”

The invention provides FGFR fusion proteins comprising a fusion partner.The fusion partner can be a molecule having a dimerization domain, suchas an Fc fragment of an immunoglobulin heavy chain. The Fc fragment maybe a wildtype Fc found in a naturally occurring antibody, a variantthereof, or a fragment thereof. In an embodiment, the Fc fragmentbelongs to the IgG1, IgG2, or IgG4 class. In an embodiment, theinvention provides fusion molecules including, but not limited to, an Fcfragment of an immunoglobulin molecule belonging to the IgG1 classand/or having a C237S mutation.

The invention provides FGFR fusion proteins comprising a linker whichconnects the first polypeptide and fusion partner. The fusion proteinsof the invention may be used interchangeably with or without such alinker. In an embodiment, the linker comprises the amino acids GS or anynucleotide sequence encoding GS. The linker may be convenient forconstructing at least the first DNA construct in attaching the nucleicacid encoding the fusion protein to the nucleic acid encoding the FGFRECD. Any linker conventional in the art may be used for this purpose tothe extent that it does not diminish the desired properties of thefusion protein.

The invention also provides multimeric FGFR fusion proteins thatcomprise more than one FGFR extracellular domain. For example, theinvention provides FGFR fusion proteins, where the fusion partnercomprises a second FGFR extracellular domain which is the same as thefirst polypeptide, forming a homodimer; or an a second FGFRextracellular domain which is different from the first polypeptide,forming a heterodimer, or a biologically active fragment of either ofthese. Such a fusion protein may increase the affinity of the fusionprotein to FGF ligand binding or expand the range of FGF ligands thatcan bind to the fusion protein. Its components may include two FGFR1extracellular domains, two FGFR2 extracellular domains, two FGFR3extracellular domains, two FGFR4 extracellular domains, or biologicallyactive fragments of any of these. It may also include heterologouscombinations of FGFR1, FGFR2, FGFR3, and FGFR4 extracellular domains, orbiologically active fragments of any of these.

The sequences of the FGFR fusion molecules of the invention are providedin the Sequence Listing and are further described in the Tables. Theirsequence designations include both published sequences and the novelfusion proteins of the invention. The types of sequences includeextracellular domains, linkers, fusion partners, deletion mutants, andother mutants.

Table 1 shows the FGFR sequences of the Sequence Listing. Column 1 showsthe internally designated identification number (Patent ID). Column 2shows the nucleotide sequence ID number for the nucleic acids encodingthe open reading frames of some of the polypeptides listed in column 3(SEQ. ID. NO. (N1)). Column 3 shows the amino acid sequence ID numberfor the polypeptide sequences (SEQ. ID. NO. (P1)). Column 4 provides adescription of the polypeptides, including the NCBI accession numberswhen applicable (Protein ID). Column 5 provides a brief description ofthe encoded protein, designating the FGFR family (Protein). Column 6provides an annotation of the protein, including a description of thevariant FGFR, when applicable (Annotation). Column 7 provides adescription of the variant or parental construct, including amino acidresidues deleted or changed, when applicable (Description).

TABLE 1 SEQ ID NOS and Protein Identification Patent SEQ. ID. SEQ. ID.ID NO. (N1) NO. (P1) Protein ID Protein Annotation Description HG1020SEQ ID SEQ ID NP_056934_1-374 FGFR1IIIc ECD only 122 NO: 1 NO: 92 HG1020SEQ ID SEQ ID NP_075594_1-285 FGFR1IIIc ECD only 123 NO: 2 NO: 93 HG1020SEQ ID SEQ ID NP_000595_1-376 FGFR1IIIc ECD only 124 NO: 3 NO: 94 HG1021SEQ ID SEQ ID NP_056934_1- FGFR1IIIc FGFR1 + linker + parental  602NO: 4 NO: 95 374_GS_1793965 Fc construct 8_233-464_C237S HG1020 SEQ IDSEQ ID NP_056934_1- FGFR1IIIc R1Mut6 del GS 125 NO: 5 NO: 96374_17939658_23 3-464_C237S HG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIcR1Mut1 del LYLEGS 127 NO: 6 NO: 97 370_17939658_23 3-464_C237S HG1020SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut2 del 126 NO: 7 NO: 98366_17939658_23 MTSPLYLEGS 3-464_C237S HG1020 SEQ ID SEQ ID NP_056934_1-FGFR1IIIc R1Mut3 del 128 NO: 8 NO: 99 365_17939658_23 VMTSPLYLEGS3-464_C237S HG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut4 del 129NO: 9 NO: 100 360_17939658_23 EERPAVMTSPL 3-464_C237S YLEGS HG1020SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut5 del 130 NO: 10 NO: 101355_17939658_23 VLEALEERPAV 3-464_C237S MTSPLYLEGS HG1020 SEQ ID SEQ IDNP_056934_1- FGFR1IIIc R1Mut7 del PA 131 NO: 11 NO: 102 374_D364-D365_17939658_2 33-464_C237S HG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIcR1Mut8 P364G 132 NO: 12 NO: 103 374_P364G_1793 9658_233- 464_C237SHG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut9 P364M 133 NO: 13NO: 104 374_P364M_1793 9658_233- 464_C237S HG1020 SEQ ID SEQ IDNP_056934_1- FGFR1IIIc R1Mut10 M367N 134 NO: 14 NO: 105 374_M367N_17939658_233- 464_C237S HG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut11P364M M367N 135 NO: 15 NO: 106 374_P364M_M36 7N_17939658_233- 464_C237SHG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut6 del GS 136 NO: 16NO: 107 285_17939658_23 3-464_C237S HG1020 SEQ ID SEQ ID NP_075594_1-FGFR1IIIc R1Mut1 del LYLEGS 138 NO: 17 NO: 108 281_17939658_233-464_C237S HG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut2 del 137NO: 18 NO: 109 277_17939658_23 MTSPLYLEGS 3-464_C237S HG1020 SEQ IDSEQ ID NP_075594_1- FGFR1IIIc R1Mut3 del 139 NO: 19 NO: 110276_17939658_23 VMTSPLYLEGS 3-464_C237S HG1020 SEQ ID SEQ IDNP_075594_1- FGFR1IIIc R1Mut4 del 140 NO: 20 NO: 111 271_17939658_23EERPAVMTSPL 3-464_C237S YLEGS HG1020  SEQ ID SEQ ID NP_075594_1-FGFR1IIIc R1Mut7 del PA 141 NO: 21 NO: 112 285_D275- D276_17939658_233-464_C237S HG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut8 P275G142 NO: 22 NO: 113 285_P275G_1793 9658_233- 464_C237S HG1020 SEQ IDSEQ ID NP_075594_1- FGFR1IIIc R1Mut9 P275M 143 NO: 23 NO: 114285_P275M_1793 9658_233- 464_C237S HG1020 SEQ ID SEQ ID NP_075594_1-FGFR1IIIc R1Mut10 M278N 144 NO: 24 NO: 115 285_M278N_1793 9658_233-464_C237S HG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut11P275M M278N 145 NO: 25 NO: 116 285_P275M_M27 8N_17939658_233- 464_C237SHG1020 SEQ ID SEQ ID NP_000595_1- FGFR1IIIc R1Mut6 del GS 146 NO: 26NO: 117 376_17939658_23 3-464_C237S HG1020 SEQ ID SEQ ID NP_000595_1-FGFR1IIIc R1Mut1 del LYLEGS 148 NO: 27 NO: 118 372_17939658_233-464_C237S HG1020 SEQ ID SEQ ID NP_000595_1- FGFR1IIIc R1Mut2 del 147NO: 28 NO: 119 368_17939658_23 MTSPLYLEGS 3-464_C237S HG1020 SEQ IDSEQ ID NP_000595_1- FGFR1IIIc R1Mut3 del 149 NO: 29 NO: 120367_17939658_23 VMTSPLYLEGS 3-464_C237S HG1020 SEQ ID SEQ IDNP_000595_1- FGFR1IIIc R1Mut4 del 150 NO: 30 NO: 121 362_17939658_23EERPAVMTSPL 3-464_C237S YLEGS HG1020 SEQ ID SEQ ID NP_000595_1-FGFR1IIIc R1Mut7 del PA 151 NO: 31 NO: 122 376_D366- D367_17939658_233-464_C237S HG1020 SEQ ID SEQ ID NP_000595_1- FGFR1IIIc R1Mut8 P366G152 NO: 32 NO: 123 376_P366G_1793 9658_233- 464_C237S HG1020 SEQ IDSEQ ID NP_000595_1- FGFR1IIIc R1Mut9 P366M 153 NO: 33 NO: 124376_P366M_1793 9658_233- 464_C237S HG1020 SEQ ID SEQ ID NP_000595_1-FGFR1IIIc R1Mut10 M369N 154 NO: 34 NO: 125 376_M369N_1793 9658_233-464_C237S HG1020 SEQ ID SEQ ID NP_000595_1- FGFR1IIIc R1Mut11P366M M369N 155 NO: 35 NO: 126 376_P366M_M36 9N_17939658_233- 464_C237SHG1020 SEQ ID SEQ ID NP_056934_1-370 FGFR1IIIc R1Mut1 del LYLEGS 157NO: 36 NO: 127 HG1020 SEQ ID SEQ ID NP_056934_1-366 FGFR1IIIc R1Mut2 del156 NO: 37 NO: 128 MTSPLYLEGS HG1020 SEQ ID SEQ ID NP_056934_1-365FGFR1IIIc R1Mut3 del 158 NO: 38 NO: 129 VMTSPLYLEGS HG1020 SEQ ID SEQ IDNP_056934_1-360 FGFR1IIIc R1Mut4 del 159 NO: 39 NO: 130 EERPAVMTSPLYLEGS HG1020 SEQ ID SEQ ID NP_056934_1-355 FGFR1IIIc R1Mut5 del 160NO: 40 NO: 131 VLEALEERPAV MTSPLYLEGS HG1020 SEQ ID SEQ ID NP_056934_1-FGFR1IIIc R1Mut7 del PA 161 NO: 41 NO: 132 374_D364-D365 HG1020 SEQ IDSEQ ID NP_056934_1- FGFR1IIIc R1Mut8 P364G 162 NO: 42 NO: 133 374_P364GHG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut9 P364M 163 NO: 43NO: 134 374_P364M HG1020 SEQ ID SEQ ID NP_056934_1- FGFR1IIIc R1Mut10M367N 164 NO: 44 NO: 135 374_M367N HG1020 SEQ ID SEQ ID NP_056934_1-FGFR1IIIc R1Mut11 P364M M367N 165 NO: 45 NO: 136 374_P364M_M36 7N HG1020SEQ ID SEQ ID NP_075594_1-281 FGFR1IIIc R1Mut1 del LYLEGS 167 NO: 46NO: 137 HG1020 SEQ ID SEQ ID NP_075594_1-277 FGFR1IIIc R1Mut2 del 166NO: 47 NO: 138 MTSPLYLEGS HG1020 SEQ ID SEQ ID NP_075594_1-276 FGFR1IIIcR1Mut3 del 168 NO: 48 NO: 139 VMTSPLYLEGS HG1020 SEQ ID SEQ IDNP_075594_1-271 FGFR1IIIc R1Mut4 del 169 NO: 49 NO: 140 EERPAVMTSPLYLEGS HG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut7 del PA 170NO: 50 NO: 141 285_D275-D276 HG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIcR1Mut8 P275G 171 NO: 51 NO: 142 285_P275G HG1020 SEQ ID SEQ IDNP_075594_1- FGFR1IIIc R1Mut9 P275M 172 NO: 52 NO: 143 285_P275M HG1020SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut10 M278N 173 NO: 53 NO: 144285_M278N HG1020 SEQ ID SEQ ID NP_075594_1- FGFR1IIIc R1Mut11P275M M278N 174 NO: 54 NO: 145 285_P275M_M27 8N HG1020 SEQ ID SEQ IDNP_000595_1-372 FGFR1IIIc R1Mut1 del LYLEGS 176 NO: 55 NO: 146 HG1020SEQ ID SEQ ID NP_000595_1-368 FGFR1IIIc R1Mut2 del 175 NO: 56 NO: 147MTSPLYLEGS HG1020 SEQ ID SEQ ID NP_000595_1-367 FGFR1IIIc R1Mut3 del 177NO: 57 NO: 148 VMTSPLYLEGS HG1020 SEQ ID SEQ ID NP_000595_1-362FGFR1IIIc R1Mut4 del 178 NO: 58 NO: 149 EERPAVMTSPL YLEGS HG1020 SEQ IDSEQ ID NP_000595_1- FGFR1IIIc R1Mut7 del PA 179 NO: 59 NO: 150376_D366-D367 HG1020 SEQ ID SEQ ID NP_000595_1- FGFR1IIIc R1Mut8 P366G180 NO: 60 NO: 151 376_P366G HG1020 SEQ ID SEQ ID NP_000595_1- FGFR1IIIcR1Mut9 P366M 181 NO: 61 NO: 152 376_P366M HG1020 SEQ ID SEQ IDNP_000595_1- FGFR1IIIc R1Mut10 M369N 182 NO: 62 NO: 153 376_M369N HG1020SEQ ID SEQ ID NP_000595_1- FGFR1IIIc R1Mut11 P366M M369N 183 NO: 63NO: 154 376_P366M_M36 9N HG1020 SEQ ID SEQ ID 182571_1-369 FGFR4FGFR4 ECD 184 NO: 64 NO: 155 HG1020 SEQ ID SEQ ID 182571_1- FGFR4FGFR4 ECD + parental  185 NO: 65 NO: 156 369_17939658_23 linker +Fcconstruct 3-464_C237S HG1021 SEQ ID SEQ ID 182571_1- FGFR4 FGFR4 ECD +no linker 610 NO: 66 NO: 157 369_nolinker_179 Fc 39658_233- 464_C237SHG1020 SEQ ID SEQ ID 13991618_1-159 FGFR4 other FGFR4 186 NO: 67 NO: 158ECD HG1020 SEQ ID SEQ ID NP_002002_1-369 FGFR4 other FGFR4 187 NO: 68NO: 159 ECD HG1020 SEQ ID SEQ ID 31372_1-369 FGFR4 other FGFR4 188NO: 69 NO: 160 ECD HG1020 SEQ ID SEQ ID 2832350_1-369 FGFR4 other FGFR4189 NO: 70 NO: 161 ECD HG1021 SEQ ID SEQ ID 182571_1- FGFR4 R4Mut1del ARYTD 616 NO: 71 NO: 162 364_17939658_23 3-464_C237S HG1021 SEQ IDSEQ ID 182571_1- FGFR4 R4Mut2 del 617 NO: 72 NO: 163 359_17939658_23AAAPEARYTD 3-464_C237S HG1021 SEQ ID SEQ ID 182571_1- FGFR4 R4Mut3 del618 NO: 73 NO: 164 354_17939658_23 DPTWTAAAPEA 3-464_C237S RYTD HG1021SEQ ID SEQ ID 182571_1- FGFR4 R4Mut4 del 619 NO: 74 NO: 165352_17939658_23 EEDPTWTAAAP 3-464_C237S EARYTD HG1021 SEQ ID SEQ ID182571_1- FGFR4 R4Mut5 del 620 NO: 75 NO: 166 351_17939658_23PEEDPTWTAAA 3-464_C237S PEARYTD HG1020 SEQ ID SEQ ID NP_056934_1-19FGFR1 leader seq for 190 NO: 76 NO: 167 FGFR1 (all three variants)HG1020 SEQ ID SEQ ID 182571_1-19 FGFR4 leader seq for 191 NO: 77 NO: 168FGFR4 HG1020 SEQ ID SEQ ID 2832350_1-21 FGFR4 leader seq for 192 NO: 78NO: 169 FGFR4 HG1020 SEQ ID SEQ ID linker_sequence linker 118 NO: 79NO: 170 HG1020 SEQ ID SEQ ID 17939658_233- Fc 119 NO: 80 NO: 171464_C237S HG1020 SEQ ID SEQ ID 34528298_241- Fc 120 NO: 81 NO: 172 468HG1020 SEQ ID SEQ ID 19684073_245- Fc 121 NO: 82 NO: 173 473 HG1020SEQ ID SEQ ID NP_000133_1-375 FGFR3IIIc ECD only FGFR3IIIc 374 NO: 83NO: 174 HG1020 SEQ ID SEQ ID NP_075254_1-310 FGFR3IIIc ECD only 375NO: 84 NO: 175 HG1021 SEQ ID SEQ ID NP_000133_1- FGFR3IIIc FGFR3IIIc +with linker 603 NO: 85 NO: 176 375_GS_1793965 GS + Fc 8_233-464_C237SHG1021 SEQ ID SEQ ID NP_000133_1- FGFR3IIIc FGFR3IIIc + no linker 604NO: 86 NO: 177 375_17939658_23 Fc 3-464_C237S HG1021 SEQ ID SEQ IDNP_000133_1- FGFR3IIIc R3Mut1 del VYAGGS 605 NO: 87 NO: 178371_17939658_23 3-464_C237S HG1021 SEQ ID SEQ ID NP_000133_1- FGFR3IIIcR3Mut2 del 606 NO: 88 NO: 179 367_17939658_23 EAGSVYAGGS 3-464_C237SHG1021 SEQ ID SEQ ID NP_000133_1- FGFR3IIIc R3Mut3 del 607 NO: 89NO: 180 366_17939658_23 DEAGSVYAGGS 3-464_C237S HG1021 SEQ ID SEQ IDNP_000133_1- FGFR3IIIc R3Mut4 del 608 NO: 90 NO: 181 361_17939658_23ELVEADEAGSV 3-464_C237S YAGGS HG1021 SEQ ID SEQ ID NP_000133_1-FGFR3IIIc R3Mut5 del 609 NO: 91 NO: 182 355_17939658_23 VLPAEEELVEA3-464_C237S DEAGSVYAGGS HG1021 SEQ ID SEQ ID NP_056934_1-374 FGFR1IIIbECD only 621 NO: 183 NO: 197 HG1021 SEQ ID SEQ ID FGFR1IIIb_1- FGFR1IIIbECD + Fc no linker 622 NO: 184 NO: 198 374_17939658_23 3-464_C237SHG1021 SEQ ID SEQ ID FGFR1IIIb_1- FGFR1IIIb R1Mut1 del LYLE 623 NO: 185NO: 199 370_17939658_23 3-464_C237S HG1021 SEQ ID SEQ ID FGFR1IIIb_1-FGFR1IIIb R1Mut2 del  624 NO: 186 NO: 200 366_17939658_23 MTSPLYLE3-464_C237S HG1021 SEQ ID SEQ ID FGFR1IIIb_1- FGFR1IIIb R1Mut3 del  625NO: 187 NO: 201 365_17939658_23 VMTSPLYLE 3-464_C237S HG1021 SEQ IDSEQ ID FGFR1IIIb_1- FGFR1IIIb R1Mut4 del 626 NO: 188 NO: 202361_17939658_23 ERPAVMTSPLY 3-464_C237S LE HG1021 SEQ ID SEQ IDFGFR1IIIb_1- FGFR1IIIb R1Mut5 del 627 NO: 189 NO: 203 355_17939658_23VLEALEERPAV 3-464_C237S MTSPLYLE HG1021 SEQ ID SEQ ID P22607_1-375FGFR3IIIb ECD only 628 NO: 190 NO: 204 HG1021 SEQ ID SEQ ID P22607_1-FGFR3IIIb ECD + Fc no linker 629 NO: 191 NO: 205 375_17939658_233-464_C237S HG1021 SEQ ID SEQ ID P22607_1- FGFR3IIIb R3Mut1 del VYAG 630NO: 192 NO: 206 371_17939658_23 3-464_C237S HG1021 SEQ ID SEQ IDP22607_1- FGFR3IIIb R3Mut2 del  631 NO: 193 NO: 207 367_17939658_23EAGSVYAG 3-464_C237S HG1021 SEQ ID SEQ ID P22607_1- FGFR3IIIb R3Mut3del  632 NO: 194 NO: 208 366_17939658_23 DEAGSVYAG 3-464_C237S HG1021SEQ ID SEQ ID P22607_1- FGFR3IIIb R3Mut4 del 633 NO: 195 NO: 209362_17939658_23 LVEADEAGSVY 3-464_C237S AG HG1021 SEQ ID SEQ IDP22607_1- FGFR3IIIb R3Mut5 del 634 NO: 196 NO: 210 355_17939658_23VLPAEEELVEA 3-464_C237S DEAGSVYAG HG1021 SEQ ID SEQ ID 15281415_1-378FGFR2b ECD only 635 NO: 211 NO: 227 HG1021 SEQ ID SEQ ID 15281415_1-FGFR2b ECD + Fc 636 NO: 212 NO: 228 378_17939658_23 3-464_C237S HG1021SEQ ID SEQ ID 15281415_1- FGFR2b ECD + 637 NO: 213 NO: 229378_GS_1793965 GS + Fc 8_233-464_C237S HG1021 SEQ ID SEQ ID 15281415_1-FGFR2b R2Mut1 del DYLE 638 NO: 214 NO: 230 374_17939658_23 3-464_C237SHG1021 SEQ ID SEQ ID 15281415_1- FGFR2b R2Mut2 del  639 NO: 215 NO: 231370_17939658_23 TASPDYLE 3-464_C237S HG1021 SEQ ID SEQ ID 15281415_1-FGFR2b R2Mut3 del  640 NO: 216 NO: 232 369_17939658_23 ITASPDYLE3-464_C237S HG1021 SEQ ID SEQ ID 15281415_1- FGFR2b R2Mut4 del 641NO: 217 NO: 233 365_17939658_23 REKEITASPDYL 3-464_C237S E HG1021 SEQ IDSEQ ID 15281415_1- FGFR2b R2Mut5 del 642 NO: 218 NO: 234 356_17939658_23VLPKQQAPGRE 3-464_C237S KEITASPDYLE HG1021 SEQ ID SEQ ID NP_000132_1-377FGFR2c ECD only 643 NO: 219 NO: 235 HG1021 SEQ ID SEQ ID NP_000132_1-FGFR2c ECD + Fc 644 NO: 220 NO: 236 377_17939658_23 3-464_C237S HG1021SEQ ID SEQ ID NP_000132_1- FGFR2c ECD + 645 NO: 221 NO: 237377_GS_1793965 GS + Fc 8_233-464_C237S HG1021 SEQ ID SEQ ID NP_000132_1-FGFR2c R2Mut1 del DYLE 646 NO: 222 NO: 238 373_17939658_23 3-464_C237SHG1021 SEQ ID SEQ ID NP_000132_1- FGFR2c R2Mut2 del  647 NO: 223 NO: 239369_17939658_23 TASPDYLE 3-464_C237S HG1021 SEQ ID SEQ ID NP_000132_1-FGFR2c R2Mut3 del  648 NO: 224 NO: 240 368_17939658_23 ITASPDYLE3-464_C237S HG1021 SEQ ID SEQ ID NP_000132_1- FGFR2c R2Mut4 del 649NO: 225 NO: 241 364_17939658_23 REKEITASPDYL 3-464_C237S E HG1021 SEQ IDSEQ ID NP_000132_1- FGFR2c R2Mut5 del 650 NO: 226 NO: 242358_17939658_23 VLPAPGREKEIT 3-464_C237S ASPDYLE HG1021 SEQ IDR1_delfragment_1 FGFR1 deleted LYLE 651 NO: 243 fragment HG1021 SEQ IDR1_delfragment_2 FGFR1 deleted PLYLE 652 NO: 244 fragment HG1021 SEQ IDR1_delfragment_3 FGFR1 deleted MTSPLYLE 653 NO: 245 fragment HG1021SEQ ID R1_delfragment_4 FGFR1 deleted AVMTSPLYLE 654 NO: 246 fragmentHG1021 SEQ ID R1_delfragment_5 FGFR1 deleted VMTSPLYLE 655 NO: 247fragment HG1021 SEQ ID R1_delfragment_6 FGFR1 deleted EERPAVMTSPL 656NO: 248 fragment YLE HG1021 SEQ ID R1_delfragment_7 FGFR1 deletedLEERPAVMTSP 657 NO: 249 fragment LYLE HG1021 SEQ ID R1_delfragment_8FGFR1 deleted KALEERPAVMT 658 NO: 250 fragment SPLYLE HG1021 SEQ IDR1_delfragment_9 FGFR1 deleted EALEERPAVMT 659 NO: 251 fragment SPLYLEHG1021 SEQ ID R1_delfragment_1 FGFR1 deleted RPVAKALEERP 660 NO: 252 0fragment AVMTSPLYLE HG1021 SEQ ID R2_delfragment_l FGFR2 deleted DYLE661 NO: 253 fragment HG1021 SEQ ID R2_delfragment_2 FGFR2 deleted PDYLE662 NO: 254 fragment HG1021 SEQ ID R2_delfragment_3 FGFR2 deletedTASPDYLE 663 NO: 255 fragment HG1021 SEQ ID R2_delfragment_4 FGFR2deleted ITASPDYLE 664 NO: 256 fragment HG1021 SEQ ID R2_delfragment_5FGFR2 deleted EITASPDYLE 665 NO: 257 fragment HG1021 SEQ IDR2_delfragment_6 FGFR2 deleted GREKEITASPDY 666 NO: 258 fragment LEHG1021 SEQ ID R2_delfragment_7 FGFR2 deleted PGREKEITASPD 667 NO: 259fragment YLE HG1021 SEQ ID R2_delfragment_8 FGFR2 deleted APGREKEITASP668 NO: 260 fragment DYLE HG1021 SEQ ID R2_delfragment_9 FGFR2 deletedPAPGREKEITAS 669 NO: 261 fragment PDYLE HG1021 SEQ ID R2_delfragment_1FGFR2 deleted QAPGREKEITAS 670 NO: 262 0 fragment PDYLE HG1021 SEQ IDR2_delfragment_1 FGFR2 deleted PKQQAPGREKEI 671 NO: 263 1 fragmentTASPDYLE HG1021 SEQ ID R3_delfragment_1 FGFR3 deleted VYAG 672 NO: 264fragment HG1021 SEQ ID R3_delfragment_2 FGFR3 deleted SVYAG 673 NO: 265fragment HG1021 SEQ ID R3_delfragment_3 FGFR3 deleted EAGSVYAG 674NO: 266 fragment HG1021 SEQ ID R3_delfragment_4 FGFR3 deleted DEAGSVYAG675 NO: 267 fragment HG1021 SEQ ID R3_delfragment_5 FGFR3 deletedADEAGSVYAG 676 NO: 268 fragment HG1021 SEQ ID R3_delfragment_6 FGFR3deleted ELVEADEAGSV 677 NO: 269 fragment YAG HG1021 SEQ IDR3_delfragment_7 FGFR3 deleted EELVEADEAGS 678 NO: 270 fragment VYAGHG1021 SEQ ID R3_delfragment_8 FGFR3 deleted AEEELVEADEA 679 NO: 271fragment GSVYAG HG1021 SEQ ID R3_delfragment_9 FGFR3 deleted PAEEELVEADE680 NO: 272 fragment AGSVYAG HG1021 SEQ ID R3_delfragment_1 FGFR3deleted GPRAAEEELVE 681 NO: 273 0 fragment ADEAGSVYAG HG1021 SEQ IDR4_delfragment_1 FGFR4 deleted RYTD 682 NO: 274 fragment HG1021 SEQ IDR4_delfragment_2 FGFR4 deleted ARYTD 683 NO: 275 fragment HG1021 SEQ IDR4_delfragment_3 FGFR4 deleted APEARYTD 684 NO: 276 fragment HG1021SEQ ID R4_delfragment_4 FGFR4 deleted AAPEARYTD 685 NO: 277 fragmentHG1021 SEQ ID R4_delfragment_5 FGFR4 deleted AAAPEARYTD 686 NO: 278fragment HG1021 SEQ ID R4_delfragment_6 FGFR4 deleted PTWTAAAPEAR 687NO: 279 fragment YTD HG1021 SEQ ID R4_delfragment_7 FGFR4 deletedDPTWTAAAPEA 688 NO: 280 fragment RYTD HG1021 SEQ ID R4_delfragment_8FGFR4 deleted EEDPTWTAAAP 689 NO: 281 fragment EARYTD HG1021 SEQ IDR4_delfragment_9 FGFR4 deleted PEEDPTWTAAA 690 NO: 282 fragment PEARYTD

Table 2 shows information characterizing sequences relating tofull-length FGFR1, FGFR3, and FGFR4 proteins. Column 1 shows the NCBIaccession number (Protein ID). Column 2 designates whether the sequencerelates to FGFR1, FGFR3, or FGFR4. Column 3 shows the predicted lengthof the polypeptide encoded by each protein (Protein Length). Column 4(Treevote) shows the result of an algorithm that predicts whether thepredicted amino acid sequence is secreted. A Treevote at or near 0indicates a low probability that the protein is secreted while aTreevote at or near 1.00 indicates a high probability that the proteinis secreted. Column 5 shows the predicted signal peptide coordinates(Signal Peptide Coords). Column 6 shows the mature protein coordinates,which refer to the coordinates of the amino acid residues of the maturepolypeptide after cleavage of the secretory leader or signal peptidesequence (Mature Protein Coords). Column 7 shows alternate predictionsof the signal peptide coordinates (Altern Signal Peptide Coords). Column8 specifies the coordinates of an alternative form of the mature protein(Altern Mature Protein Coords). The alternate coordinates result fromalternative predictions of the signal peptide cleavage site; theirpresence may, for example, depend on the host used to express thepolypeptides. Column 9 specifies the number of transmembrane domains(TM). Columns 10 and 11 provide the coordinates of the transmembrane andnon-transmembrane sequences of the polypeptides. The transmembranecoordinates (TM Coords) designate the transmembrane domains of themolecule. The non-transmembrane coordinates (non-TM Coords) refer to theprotein segments not located in the membrane; these can includeextracellular, cytoplasmic, and luminal sequences. Coordinates arelisted in terms of the amino acid residues beginning with “1” for thefirst amino acid residue at the N-terminus of the full-lengthpolypeptide.

TABLE 2 Characterization of FGFR Sequences Signal Mature Protein PeptideProtein Altern Signal Altern Mature TM Non-TM Protein ID Protein LengthTreevote Coords Coords Peptide Coords Protein Coords TM Coords CoordsNP_056934 FGFR1 820 0 (1-19) (20-820) (11-23)  (24-820) 1 (373-395)(1-372) (9-21) (22-820) (396-820)  NP_075594 FGFR1 731 0 (1-19) (20-731)(11-23)  (24-731) 1 (284-306) (1-283) (9-21) (22-731) (307-310) NP_000595 FGFR1 822 0 (1-19) (20-822) (11-23)  (24-822) 1 (375-397)(1-374) (9-21) (22-822) (398-822)  NP_075254 FGFR3 694 0.93 (1-19)(20-694) (3-15) (16-694) 0 (1-694) (8-20) (21-694) (10-22)  (23-694)NP_000133 FGFR3 806 0.03 (1-19) (20-806) (3-15) (16-806) 2 (373-395)(1-372) (8-20) (21-806) (537-559) (396-536)  (10-22)  (23-806)(560-806)  FGFR3- FGFR3 606 0.99 (1-16) (17-606) (8-20) (21-606) 0(370-392) (1-606) IIIc-Fc (6-18) (19-606) (3-15) (16-606) (2-14)(15-606) 182571 FGFR4 802 0.99 (1-18) (19-802) (1-13) (14-802) 0 (1-802)(4-16) (17-802) (3-15) (16-802) 13991618 FGFR4 592 0  (1-592) 0 (1-592)NP_002002 FGFR4 802 1 (1-18) (19-802) (1-13) (14-802) 0 (1-802) (4-16)(17-802) (3-15) (16-802) 2832350 FGFR4 802 0.98 (1-18) (19-802) (1-13)(14-802) 0 (1-802) (3-15) (16-802) (4-16) (17-802) 31372 FGFR4 802 1(1-18) (19-802) (1-13) (14-802) 0 (1-802) (4-16) (17-802) (3-15)(16-802)

Nucleic Acid Molecules Encoding FGFR Fusion Molecules

The present invention provides nucleic acid molecules that comprisepolynucleotide sequences that encode the FGFR fusion proteins of theinvention. These nucleic acid molecules can be constructed withrecombinant DNA techniques conventional in the art. The nucleic acidmolecules include molecules relevant to the FGFR1-IIIb ECD, such asthose provided in SEQ ID NOS: 183-189; those relevant to FGFR1-IIIc ECD,such as those provided in SEQ ID NOS: 1-63; those relevant to FGFR2-IIIbECD, such as those provided in SEQ ID NOS: 211-218; those relevant toFGFR2-IIIc ECD, such as those provided in SEQ ID NOS: 219-226; thoserelevant to FGFR3-IIIb ECD, such as those provided in SEQ ID NOS:190-196; those relevant to FGFR3-IIIc ECD, such as those provided in SEQID NOS: 83-91; and those relevant to FGFR4 ECD, such as those providedin SEQ ID NOS: 64-78.

The nucleic acid molecules of the invention can include polynucleotidesequences that encode all or part of the ECD of an FGFR polypeptide,with or without its native homologous secretory leader sequence. If ahomologous secretory leader sequence is not used in the construction ofthe nucleic acid molecule, then another secretory leader sequence may beused, for example, any one of the leader sequences described in PCTUS06/02951.

Typically, the nucleic acid molecule encoding the gene of interest, theFGFR ECD, is inserted into an expression vector, suitable for expressionin a selected host cell, at a linker site and the nucleic acid moleculeencoding the fusion partner is inserted at the site following the FGFRECD such that they are in-frame when the nucleic acid molecule istranscribed and translated.

FGFR Fusion Molecule Expression and Production

Vectors

The invention provides genetically engineered recombinant vectorscomprising nucleic acid molecules encoding the fusion proteins of theinvention, recombinant host cells comprising the recombinant vectors,the nucleic acid molecules encoding the fusion proteins of theinvention, and the production of FGFR fusion proteins and fragmentsthereof. Vectors of the invention include those that are suitable forexpression in a selected host, whether prokaryotic or eukaryotic, forexample, phage, plasmid, and viral vectors. Viral vectors may be eitherreplication competent or replication defective retroviral vectors. Viralpropagation generally will occur only in complementing host cellscomprising replication defective vectors. Vectors of the invention maycomprise Kozak sequences (Lodish et al., Molecular Cell Biology, 4^(th)ed., 1999) and may also contain the ATG start codon of an FGFRextracellular domain. Vectors of the invention include “minicircle”vectors, which are described in greater detail below.

Copy number and positional effects are considered in designingtransiently and stably expressed vectors. Copy number can be increasedby, for example, dihydrofolate reductase amplification. Positionaleffects can be optimized by, for example, Chinese hamster elongationfactor-1 vector pDEF38 (CHEF1), ubiquitous chromatin opening elements(UCOE), scaffold/matrix-attached region of human (S/MAR), and artificialchromosome expression (ACE) vectors, as well as by using site-specificintegration methods known in the art. The expression constructscontaining the vector and gene of interest will further contain sitesfor transcription initiation, termination, and, in the transcribedregion, a ribosome binding site for translation. The coding portion ofthe transcripts expressed by the constructs can include a translationinitiating codon at the beginning and a termination codon (UAA, UGA, orUAG) appropriately positioned at the end of the polypeptide to betranslated.

Considering the above-mentioned factors, vectors suitable for expressingFGFR fusion molecules in bacteria include pTT vectors, available fromBiotechnology Research Institute (Montreal, Canada), pQE70, pQE60, andpQE-9, available from Qiagen (Mississauga, Ontario, Canada); vectorsderived from pcDNA3, available from Invitrogen (Carlsbad, Calif.); pBSvectors, Phagescript vectors, Bluescript vectors, pNH8A, pNH6a, pNH18A,pNH46A, available from Stratagene (La Jolla, Calif.); and ptrc99a,pKK223-3, pKK233-3, pDR540, pRIT5 available from Pharmacia (Peapack,N.J.). Among suitable eukaryotic vectors are pWLNEO, pSV2CAT, pOG44,pXT1, and pSG available from Stratagene (La Jolla, Calif.); and pSVK3,pBPV, pMSG and pSVL, available from Pharmacia (Peapack, N.J.).

Vectors for expressing FGFR fusion molecules include those comprising apTT vector backbone (Durocher et al., Nucl. Acids Res. 30:E9 (2002)).Briefly, the backbone of a pTT vector may be prepared by obtainingpIRESpuro/EGFP (pEGFP) and pSEAP basic vector(s), for example fromClontech (Palo Alto, Calif.), and pcDNA3.1, pCDNA3.1/Myc-(His)₆ andpCEP4 vectors can be obtained from, for example, Invitrogen (Carlsbad,Calif.). As used herein, the pTT5 backbone vector can generate apTT5-Gateway vector and be used to transiently express proteins inmammalian cells. The pTT5 vector can be derivatized to pTT5-A, pTT5-B,pTT5-D, pTT5-E, pTT5-H, and pTT5-I, for example. As used herein, thepTT2 vector can generate constructs for stable expression in mammaliancell lines.

A pTT vector can be prepared by deleting the hygromycin (BsmI and SalIexcision followed by fill-in and ligation) and EBNA1 (ClaI and NsiIexcision followed by fill-in and ligation) expression cassettes. TheColEI origin (FspI-SalI fragment, including the 3′ end of theβ-lactamase open reading frame (ORF) can be replaced with a FspI-SalIfragment from pcDNA3.1 containing the pMBI origin (and the same 3′ endof β-lactamase ORF). A Myc-(His)₆ C-terminal fusion tag can be added toSEAP (HindIII-HpaI fragment from pSEAP-basic) following in-frameligation in pcDNA3.1/Myc-His digested with HindIII and EcoRV. Plasmidscan subsequently be amplified in E. coli (DH5α) grown in LB medium andpurified using MAXI prep columns (Qiagen, Mississauga, Ontario, Canada).To quantify, plasmids can be subsequently diluted in, for example, 50 mMTris-HCl pH 7.4 and absorbencies can be measured at 260 nm and 280 nm.Plasmid preparations with A₂₆₀/A₂₈₀ ratios between about 1.75 and about2.00 are suitable for producing the FGFR constructs.

The expression vector pTT5 allows for extrachromosomal replication ofthe cDNA driven by a cytomegalovirus (CMV) promoter. The plasmid vectorpCDNA-pDEST40 is a Gateway-adapted vector which can utilize a CMVpromoter for high-level expression. SuperGlo GFP variant (sgGFP) can beobtained from Q-Biogene (Carlsbad, Calif.). Preparing a pCEP5 vector canbe accomplished by removing the CMV promoter and polyadenylation signalof pCEP4 by sequential digestion and self-ligation using SalI and XbaIenzymes resulting in plasmid pCEP4Δ. A GblII fragment from pAdCMV5(Massie et al., J. Virol. 72:2289-2296 (1998)), encoding theCMV5-poly(A) expression cassette ligated in BglII-linearized pCEP4Δ,resulting in the pCEP5 vector.

Vectors for expressing FGFR fusion molecules can include thosecomprising vectors optimized for use in CHO-S or CHO-S-derived cells,such as pDEF38 (CHEF1) and similar vectors (Running Deer et al.,Biotechnol. Prog. 20:880-889 (2004). The CHEF vectors contain DNAelements that lead to high and sustained expression in CHO cells andderivatives thereof. They may include, but are not limited to, elementsthat prevent the transcriptional silencing of transgenes.

FGFR polynucleotide vectors may be joined to a selectable marker forpropagation in a host. Generally, a selectable marker allows theselection of transformed cells based on their ability to thrive in thepresence or absence of a chemical or other agent that inhibits anessential cell function. The selectable markers confer a phenotype on acell expressing the marker, so that the cell can be identified underappropriate conditions. Suitable markers, therefore, include genescoding for proteins which confer drug resistance or sensitivity thereto,impart color to, or change the antigenic characteristics of those cellstransfected with a molecule encoding the selectable marker, when thecells are grown in an appropriate selective medium.

Suitable selectable markers include dihydrofolate reductase or G418 forneomycin resistance in eukaryotic cell culture; and tetracycline,kanamycin, or ampicillin resistance genes for culturing in E. coli andother bacteria. Suitable selectable markers also include cytotoxicmarkers and drug resistance markers, whereby cells are selected by theirability to grow on media containing one or more of the cytotoxins ordrugs; auxotrophic markers, by which cells are selected for theirability to grow on defined media with or without particular nutrients orsupplements, such as thymidine and hypoxanthine; metabolic markers forwhich cells are selected, for example, for ability to grow on definedmedia containing a defined substance, for example, an appropriate sugaras the sole carbon source; and markers which confer the ability of cellsto form colored colonies on chromogenic substrates or cause cells tofluoresce.

As mentioned above, vectors for the expression of FGFR fusion proteinscan also be constructed in proteins retroviral vectors. One such vector,the ROSAβ_(geo) retroviral vector, which maps to mouse chromosome six,was constructed with the reporter gene in reverse orientation withrespect to retroviral transcription, downstream of a splice acceptorsequence (U.S. Pat. No. 6,461,864; Zambrowicz et al., Proc. Natl. Acad.Sci. 94:3789-3794 (1997)). Infecting embryonic stem (ES) cells withROSAβ_(geo) retroviral vector resulted in the ROSAβ_(geo26) (ROSA26)mouse strain by random retroviral gene trapping in the ES cells.

A DNA insert comprising an FGFR fusion molecule can be operativelylinked to an appropriate promoter, such as the phage lambda PL promoter;the E. coli lac, trp, phoA, and tac promoters; the SV40 early and latepromoters; and promoters of retroviral LTRs. Suitable promoters alsoinclude the pCMV vector with an enhancer, pcDNA3.1; the pCMV vector withan enhancer and an intron, pCIneo; the pCMV vector with an enhancer, anintron, and a tripartate leader, pTT2, and CHEF1. Other suitablepromoters will be known to the skilled artisan. The promoter sequencesinclude the minimum number of bases or elements necessary to initiatetranscription of a gene of interest at levels detectable abovebackground. Within the promoter sequence may be a transcriptioninitiation site, as well as protein binding domains (consensussequences) responsible for the binding of RNA polymerase. Eukaryoticpromoters of the invention will often, but not always, contain “TATA”boxes and “CAT” boxes.

The invention provides vectors for the in vivo expression of FGFR fusionmolecules in animals, including humans, under the control of a promoterthat functions in a tissue-specific manner. For example, promoters thatdrive the expression of FGFR fusion proteins of the invention may beliver-specific, as described in PCT/US06/00668.

A region of additional amino acids, particularly charged amino acids,may be added to the N-terminus of the polypeptide to improve stabilityand persistence in the host cell purification throughout and subsequenthandling and storage. Also, amino acid moieties may be added to thepolypeptide to facilitate purification. Such amino acids may or may notbe removed prior to the final preparation of the polypeptide. The FGFRfusion proteins of the invention can be fused to marker sequences, suchas a peptide, that facilitates purification of the fused polypeptide.The marker amino acid sequence may be a hexa-histidine peptide such asthe tag provided in a pQE vector (Qiagen, Mississauga, Ontario, Canada),among others, many of which are commercially available. As described inGentz et al., Proc. Natl. Acad. Sci. 86:821-824 (1989), for instance,hexa-histidine provides for convenient purification of the fusionprotein. Another peptide tag useful for purification, the hemagglutininHA tag, corresponds to an epitope derived from the influenzahemagglutinin protein (Wilson et al., Cell 37:767-778 (1984)). Any ofthe above markers can be engineered using the polynucleotides or thepolypeptides of the present invention.

The expression constructs of the invention will further contain sitesfor transcription initiation, termination, and, in the transcribedregion, a ribosome binding site for translation. The coding portion ofthe transcripts expressed by the constructs can include a translationinitiating codon at the beginning and a termination codon (UAA, UGA, orUAG) appropriately positioned at the end of the polypeptide to betranslated.

Host Cells

FGFR fusion proteins of the invention can be expressed by and producedfrom prokaryotic cells, such as bacterial cells and eukaryotic cells,such as fungal cells, plant cells, insect cells, and mammalian cells,according to procedures known in the art, for example, as shown in theexamples and figures that follow. FGFR fusion proteins can be expressedby and produced from bacterial E. coli cells; Cos 7 cells; mammaliankidney epithelial 293 cells; and Chinese Hamster Ovary (CHO) cells,including CHO-S and DG44 cells, which are derived from CHO cells. Theycan also be produced in vivo in animals, engineered or transfected withthe nucleic acid molecules encoding the fusion proteins. For example,mice injected with DNA encoding FGFR fusion molecules can express FGFRfusion molecules following tail vein transfection (TVT).

Introduction of the FGFR fusion proteins into the host cell can beaccomplished by calcium phosphate transfection, DEAE-dextran mediatedtransfection, cationic lipid-mediated transfection, electroporation,transduction, infection, or other known methods. Such methods aredescribed in many standard laboratory manuals, such as Sambrook et al.,Molecular Cloning, A Laboratory Manual. 3^(rd) ed. Cold Spring HarborLaboratory Press (2001). FGFR fusion proteins of the invention can betransiently or stably transfected into the host cells, as described ingreater detail below. FGFR fusion proteins of the invention can bepurified from host cells grown either in adherent culture or insuspension, and, as shown in greater detail below, can retain thebiological properties of FGFR.

Host cells of the invention can express proteins and polypeptides inaccordance with conventional methods, the method depending on thepurpose for expression. For large scale production of the protein, aunicellular organism, such as E. coli, B. subtilis, S. cerevisiae;insect cells in combination with baculovirus vectors; or cells of ahigher organism such as vertebrates, for example mammalian 293(including 293-6E), CHO (including DG44), or COS 7 cells, can be used asthe expression host cells. In some situations, it is desirable toexpress eukaryotic genes in eukaryotic cells, where the encoded proteinwill benefit from native folding and post-translational modifications,such as glycosylation.

Accordingly, the invention provides a recombinant host cell thatcomprises nucleic acid molecules encoding the FGFR fusion proteins,vectors comprising such nucleic acid molecules, or FGFR fusion proteinsand cultures containing such. These host cells may produce FGFR1, FGFR2,FGFR3, and FGFR4 fusion proteins of the invention. For example, they mayproduce FGFR-F_(c) fusion proteins and variants and fragments thereof.The host cells may be suitable for transient transfection and for stabletransfection. FGFR fusion proteins expressed by any of the methodsdescribed herein may be detected by methods known in the art.

The post-translational glycosylation of the fusion proteins of theinvention may vary according to their production source, as described ingreater detail below. The glycosylation profile of a protein can affectits properties and/or function. Accordingly, the invention providesrecombinant FGFR fusion proteins with or without altered glycosylationprofiles compared to the naturally-occurring forms. They may be producedin different host cells. For example, unglycosylated FGFR fusionproteins can be produced from E. coli. A form of glycosylated FGFRfusion protein can be produced in yeast cells, such as Saccharomycescerevisae or Pichia pastoris, or fungal cells such as Aspergillus. Aform of glycosylated FGFR fusion protein can be produced in plants, suchas rice, wheat, oats, etc. form of glycosylated FGFR protein can beproduced in mammalian cells, such as 293 cells or CHO cells orderivatives thereof. For example, the invention provides mutantconstructs with additional arginine residues for the attachment ofN-linked sugars. These constructs may comprise point mutations witharginine residues or may have larger substitutions with regions thatinclude arginine residues. The invention also provides mutant constructswith omitted arginine residues. Glycosylation mutants of the inventioncan be made by altering the naturally-occurring sequences using methodsknown to those of skill in the art.

Recombinant host cells of the invention are cultured under conditionsconventional in the art, including both inducible and non-inducibleconditions. The FGFR fusion proteins may be made inside the cells, suchas in inclusion bodies, for example, when the host cell is an E. colicell, or they may be secreted into the cell culture, such as when thehost cells are mammalian cells and the proteins are expressed usingmammalian expression systems, for example, using a secretory leadersequence. The invention provides cell cultures comprising the FGFRfusion protein whether the FGFR fusion protein is present in the culturemedium or residing inside the cells.

Purification of FGFR Fusion Proteins

The invention provides methods of purifying FGFR fusion proteins using acombination of techniques, each of which is conventional in the art.These techniques include, but are not limited to, the use of affinitymatrices and hydrophobic interaction chromatography, for example,affinity chromatography. Suitable affinity ligands include any ligandsof the FGFR extracellular domain or of the fusion partner, or antibodiesthereto. For example, a Protein A, Protein G, Protein A/G, or anantibody affinity column may be used to bind to an Fc fusion partner topurify the FGFR fusion proteins. Antibodies to the FGFR portion of thefusion protein or to the fusion partner may also be used to purify thefusion protein. Hydrophobic interactive chromatography is also suitablefor purifying FGFR fusion proteins of the invention. For example, abutyl or phenyl column may be used. Other methods of purification knownto those skilled in the art may also be suitable for purifying the FGFRfusion molecules of the invention.

Protein A affinity chromatography may be used to purify FGFR fusionproteins of the invention comprising an Fc domain. Protein A is a cellwall component produced by several strains of Staphylococcus aureus andcan be made in a recombinant fashion. It consists of a singlepolypeptide chain weighing approximately 42,000 daltons and containslittle or no carbohydrate. Protein A binds specifically to the Fc regionof most immunoglobulin molecules, including IgG (Sjoquist et al., Eur.J. Biochem. 29:572-578 (1972); Hjelm et al., Eur. J. Biochem. 57:395-403(1975)).

Protein G affinity chromatography may also be used to purify FGFR fusionproteins of the invention comprising an Fc domain. Protein G is abacterial cell wall protein produced by group G streptococci and canalso be made in a recombinant fashion. Like Protein A, Protein G bindsto most mammalian immunoglobulins, primarily through their Fc regions(Bjorck et al., J. Immunol. 133:969-974 (1984); Guss et al., EMBO J.5:1567-1575 (1986) Åkerström et al., J. Biol. Chem. 261:10,240-10,247(1986)). Affinity chromatography using chimeric Fc binding molecules mayfurther be used to purify FGFR fusion proteins of the inventioncomprising an Fc domain. For example, Protein A/G is a geneticallyengineered protein that combines the IgG binding profiles of bothProtein A and Protein G. Protein A/G is a gene fusion product, which canbe secreted from, inter alia, nonpathogenic Bacillus. Protein A/Gtypically weighs approximately 50,000 daltons and was designed tocontain four Fc binding domains from Protein A and two from Protein G(Sikkema, Amer. Biotech. Lab. 7:42 (1989); Eliasson et al., J. Biol.Chem. 263:4323-4327 (1988).

Hydrodynamic Tail Vein Transfection (TVT)

The invention provides expression of FGFR fusion proteins in animals,following a hydrodynamics-based procedure of tail vein injection (Liu,F. et al., Gene Ther. 6:1258-1266 (1999); U.S. Pat. No. 6,627,616; andZhang et al., Hum. Gene Ther. 10:1735 (1999). This technique providesfor production of the FGFR fusion protein in vivo after administeringthe nucleic acid molecule encoding the fusion protein produced in amini-circle vector construct. Serum from such injected animalscontaining the fusion protein may be used to further characterize theprotein, without first having to produce and purify the fusion proteinfrom cell culture expression systems.

In an embodiment, the invention provides vectors comprising nucleic acidmolecules encoding an FGFR fusion protein for administration to animalsand FGFR fusion proteins made thereby, following hydrodynamic injectionof minicircle DNA comprising such nucleic acid molecules. Vectors forinjection can be constructed, for example, by the system described inChen et al., Mol. Ther. 8:495-500 (2003) and U.S. Pat. Appl. No.2004/0214329 A1. In brief, an expression cassette for an FGFR gene isflanked by attachment sites for a recombinase, which is expressed in aninducible fashion in a portion of the vector sequence outside of theexpression cassette. Following recombination, the E. coli produce aminicircle vector comprising an expression cassette with an FGFR fusionprotein gene. The vector as described in Chen et al. can be modified byinserting the nucleic acid molecule encoding the FGFR fusion proteinfollowing the intron present in the vector, instead of in the midst ofthe introns.

Minicircle DNA vectors can be prepared with plasmids similar topBAD.φC31.hFIX and pBAD.φC31.RHB and used to transform E. coli.Recombinases known in the art, for example, lambda and cre, are usefulin the minicircle vectors. The expression cassettes may contain sitesfor transcription initiation, termination, and, in the transcribedregion, a ribosome binding site for translation. The coding portion ofthe transcripts expressed by the constructs can include a translationinitiating codon at the beginning and a termination codon (UAA, UGA, orUAG) appropriately positioned at the end of the polypeptide to betranslated. The plasmids may include at least one selectable marker, forexample, dihydrofolate reductase, G418, or a marker of neomycinresistance for eukaryotic cell culture; and tetracycline, kanamycin, orampicillin resistance genes for culturing in E. coli and otherprokaryotic cell culture. The minicircle producing plasmids may includeat least one origin of replication to allow for the multiplication ofthe vector in a suitable eukaryotic or a prokaryotic host cell. Originsof replication are known in the art, as described, for example, in GenesII, Lewin, B., ed., John Wiley & Sons, New York (1985). The FGFR fusionproteins produced from minicircles can also be fused to markersequences, as described above.

Fusion Partners and Conjugates

Gene manipulation techniques have enabled the development and use ofrecombinant therapeutic proteins with fusion partners that impartdesirable pharmacokinetic properties. FGFR polypeptides, including theirimmunogenic epitopes and other fragments, can be combined withheterologous molecules, resulting in therapeutically useful fusionmolecules. The invention provides fusion molecules comprising theextracellular domain of any of FGFR1, FGFR2, FGFR3, and FGFR4. Itprovides fusion partners capable of imparting favorable pharmacokineticsand/or pharmacodynamics to the FGFR. In an embodiment, the inventionprovides a fusion molecule comprising all or a part of the extracellulardomain of FGFR1-IIIb, FGFR1-IIIc, FGFR2-IIIb, FRFR2-IIIc, FGFR3-IIIb,FGFR3-IIIc, FGFR4, or fragments thereof and a fusion partner, such as anantibody Fc domain.

FGFRs are expressed in many normal tissues and many cell types expressmore than one FGFR. In view of this, it is not obvious how a therapeuticwhich targets FGFR can be devised to last long enough in the circulationof a treated subject without causing harm to the normal tissues.

Fusion molecules of the invention have an increased half-life in vivo,as compared to FGFR extracellular domains. The prolonged half-life ofthe FGFR fusion molecules described herein can require lower doses and aless-frequent dosing regimen than FGFRs alone. The resulting decreasedfluctuation of FGFR serum levels can improve the safety and tolerabilityof FGFR therapeutics.

The fusion partner can be linked to the C-terminus of the FGFR, or,alternatively, the FGFR can be linked to the C-terminus of the fusionpartner. The fusion partner may comprise a linker, for example, apeptide linker, which may or may not comprise an enzyme cleavage site.The fusion partner may also comprise a molecule that extends the in vivohalf-life by imparting improved receptor binding to FGFR within anacidic intracellular compartment, for example, an acid endosome or alysosome.

Fusion partners of the invention include polymers, polypeptides,lipophilic moieties, and succinyl groups. Examples of polypeptide fusionpartners include serum albumin and the antibody Fc domain. Polymerfusion partners may comprise one or more polyethylene glycol moieties,branched or linear chains. Lipophilic fusion partners may increase theskin permeability of the fusion molecule.

Oligomerization Domain Fusion Proteins

Oligomerization offers functional advantages to a fusion protein,including multivalency, increased binding strength, and the combinedfunction of different domains. These features are seen in naturalproteins and may also be introduced by protein engineering. Accordingly,the invention provides an FGFR fusion molecule, wherein the fusionpartner comprises an oligomerization domain, for example, a dimerizationdomain. Suitable oligomerization domains include coiled-coil domains,including alpha-helical coiled-coil domains; collagen domains;collagen-like domains, and dimeric immunoglobulin domains. Suitablecoiled-coil polypeptide fusion partners of the invention includetetranectin coiled-coil domain, the coiled-coil domain of cartilageoligomeric matrix protein; angiopoietin coiled-coil domains; and leucinezipper domains. FGFR fusion molecules with collagen or collagen-likeoligomerization domains as fusion partner may comprise, for example,those found in collagens, mannose binding lectin, lung surfactantproteins A and D, adiponectin, ficolin, conglutinin, macrophagescavenger receptor, and emilin.

Antibody Fc Domain Fusion Proteins

In an embodiment, the invention provides fusion molecules having an Fcimmunoglobulin domain. The FGFR fusion proteins of the invention cancomprise Fc, various domains of the constant regions of the heavy orlight chains of mammalian immunoglobulins and/or the first two domainsof the human CD4 polypeptide.

In an embodiment, the human Fc domain fusion partner comprises theentire Fc domain. In an embodiment it comprises one or more fragments ofthe Fc domain. For example, it may comprise a hinge and the CH2 and CH3constant domains of a human IgG, for example, human IgG1, IgG2, or IgG4.The invention provides an FGFR fusion protein wherein the fusion partneris a variant Fc polypeptide or a fragment of a variant Fc polypeptide.The variant Fc may comprise a hinge, CH2, and CH3 domains of human IgG2with a P331S mutation, as described in U.S. Pat. No. 6,900,292.

In an embodiment, a fusion protein of the invention may be a homodimericprotein linked through cysteine residues in the hinge region of IgG Fc,resulting in a molecule similar to an IgG molecule, but without CH1domains and light chains.

Methods of making fusion proteins are well-known to the skilled artisan.In an embodiment, the Fc fusion partner of the invention comprises anamino acid sequence of any of SEQ ID NO: 171, SEQ ID NO: 172, and SEQ IDNO: 173.

Albumin Fusion Proteins

The invention provides an FGFR fusion molecule with an albumin fusionpartner comprising albumin from human serum (human serum albumin or“HSA”), one or more fragments of albumin, a peptide that binds albumin,and/or a molecule that conjugates with a lipid or other molecule thatbinds albumin. In an embodiment, an FGFR-HSA fusion molecule may beprepared as described herein and as further described in U.S. Pat. No.6,686,179 with respect to an interferon alpha-HSA fusion molecule.

Dimeric FGFR Fusion Proteins

The invention provides FGFR fusion proteins, wherein the fusion partnercomprises an FGFR extracellular domain or active fragment thereof. Forexample, the fusion protein may comprise two FGFR1, FGFR2, FGFR3, orFGFR4 extracellular domains or biologically active fragments thereof.The fusion molecule may also comprise heterologous combinations of twodifferent FGFR extracellular domains or biologically active fragmentsthereof, as described in greater detail above.

In an embodiment, the FGFR fusion protein comprises an extracellulardomain of an FGFR and/or one of its active fragments and furthercomprises a fusion partner comprising a dimerization domain as well asan FGFR extracellular domain. When the fusion partner comprises adimerization domain, such as an Fc domain or an active fragment thereof,the FGFR fusion protein expressed in a mammalian cell expression systemmay naturally form a dimer during the production process.

Fusion Proteins with Pegylated Moieties

In addition to the recombinant molecules described above, the inventionprovides an FGFR fusion molecule, wherein the fusion partner comprises apolymer, such as a polyethylene glycol (PEG) moiety. PEG moieties of theinvention may be branched or linear chain polymers. In an embodiment,the present invention contemplates a chemically derivatized polypeptidewhich includes mono- or poly- (e.g., 2-4) PEG moieties. Pegylation maybe carried out by any of the pegylation reactions known in the art.Methods for preparing a pegylated protein product are generally known inthe art. Optimal reaction conditions will be determined on a case bycase basis, depending on known parameters and the desired result.

There are a number of PEG attachment methods available to those skilledin the art, for example, EP 0 401 384; Malik et al., Exp. Hematol.,20:1028-1035 (1992); Francis, Focus on Growth Factors, 3:4-10 (1992); EP0 154 316; EP 0 401 384; WO 92/16221; WO 95/34326; and the otherpublications cited herein that relate to pegylation.

Pegylation may be performed via an acylation reaction or an alkylationreaction with a reactive polyethylene glycol molecule. Thus, proteinproducts of the present invention include pegylated proteins wherein thePEG groups are attached via acyl or alkyl groups. Such products may bemono-pegylated or poly-pegylated (for example, those containing 2-6 or2-5 PEG groups). The PEG groups are generally attached to the protein atthe α- or ε-amino groups of amino acids, but it is also contemplatedthat the PEG groups could be attached to any amino group attached to theprotein that is sufficiently reactive to become attached to a PEG groupunder suitable reaction conditions.

Pegylation by acylation generally involves reacting an active esterderivative of PEG with a polypeptide of the invention. For acylationreactions, the polymer(s) selected typically have a single reactiveester group. Any known or subsequently discovered reactive PEG moleculemay be used to carry out the pegylation reaction. An example of asuitable activated PEG ester is PEG esterified to N-hydroxysuccinimide(NHS). As used herein, acylation is contemplated to include, withoutlimitation, the following types of linkages between the therapeuticprotein and a polymer such as PEG: amide, carbamate, urethane, and thelike, see for example, Chamow, Bioconjugate Chem., 5:133-140 (1994).Reaction conditions may be selected from any of those known in thepegylation art or those subsequently developed, but should avoidconditions such as temperature, solvent, and pH that would inactivatethe polypeptide to be modified.

Pegylation by acylation will generally result in a poly-pegylatedprotein. The connecting linkage may be an amide. The resulting productmay be substantially only (e.g., >95%) mono, di- or tri-pegylated.However, some species with higher degrees of pegylation may be formed inamounts which depend on the specific reaction conditions used. Ifdesired, more purified pegylated species may be separated from themixture (particularly unreacted species) by standard purificationtechniques, including among others, dialysis, salting-out,ultrafiltration, ion-exchange chromatography, gel filtrationchromatography, and electrophoresis.

Pegylation by alkylation generally involves reacting a terminal aldehydederivative of PEG with a polypeptide in the presence of a reducingagent. For the reductive alkylation reaction, the polymer(s) selectedshould have a single reactive aldehyde group. An exemplary reactive PEGaldehyde is polyethylene glycol propionaldehyde, which is water stable,or mono C1-C10 alkoxy or aryloxy derivatives thereof, see for example,U.S. Pat. No. 5,252,714.

Variant and Mutant Polypeptides

The FGFR fusion proteins of the invention can be made by proteinengineering to improve or alter the native characteristics of FGFRfusion proteins. Recombinant DNA technology known to those skilled inthe art can be used to create novel mutant proteins or “muteins,”including single or multiple amino acid substitutions, deletions, andadditions. Such modified polypeptides can possess properties desirablein a therapeutic agent, such as enhanced activity or increasedstability. In addition, they may be purified in higher yields and bemore water-soluble than the corresponding natural polypeptide, at leastunder certain purification and storage conditions.

FGFR ECD Mutants

As mentioned above, the invention provides polypeptide fusion moleculeshaving one or more residues deleted from the amino and/or carboxylterminus of the amino acid sequences of the FGFR extracellular domains.For example, the invention provides deletion mutations of FGFRextracellular domains with deletions in the C-terminal region. Theinvention provides deletion mutants missing one or more amino acids inthe region N-terminally adjacent to the transmembrane domain.

In an embodiment, the invention provides FGFR fusion proteins comprisingvariants of the ECD of wildtype FGFR polypeptides, where the variantshave deletions or point mutations in the C-terminus of the ECD, forexample, in the region of the MMP-2 cleavage site. These variants may bemore resistant to cleavage by MMP-2 than wildtype FGFR extracellulardomains. In an embodiment, the invention provides FGFR extracellulardomains which are deletion mutants that have the MMP-2 cleavage siteremoved and which are more resistant to cleavage by MMP-2 than wildtypeFGFR extracellular domains. For example, the invention provides deletionmutants of the FGFR extracellular domains in that region at theC-terminus of the IgIII domain and N-terminal to the Fc domain. Any oneor more amino acids of any of the seven FGFR extracellular domains inthis region may be deleted or, otherwise mutated. By way of example, theinvention provides deletion mutants of FGFR1, FGFR2, FGFR3, and FGFR4corresponding to R1Mut1, R1Mut2, R1Mut3, and R1Mut4, shown in FIG. 1A;R1Mut7, as shown in FIG. 1B; and R4Mut1, R4Mut2, R4Mut3, R4Mut4, andR4Mut5, as shown in FIG. 2. These variants, as well as their parental,unmutated polypeptides, all bind at least one FGF ligand. Theligand-binding characteristics of these mutants, as well as their parentFGFRs, can be determined by binding assays known in the art.

In an embodiment, the invention provides an FGFR fusion moleculecomprising a first molecule that comprises one or more solubleextracellular domain of an FGFR and/or a biologically active fragmentthereof and a second molecule, wherein the second molecule confers anextended half-life to the first molecule in an animal, wherein thesecond molecule is other than a naturally occurring Fc polypeptide, andwherein the fusion molecule is a variant Fc polypeptide.

When FGFR1-IIIc-Fc fusion protein was produced in host cells, injectedinto animals, and examined by gel electrophoresis, it was observed thatFGFR1-IIIc-Fc was partially cleaved both in vivo and in vitro. Degradedfragments in the cell culture media and serum samples were consistentwith the size of fragments predicted following cleavage of the Fc fusionpartner from the fusion protein. MMP-2 added exogenously toFGFR1-IIIc-Fc in vitro reproduced the degraded fragments observed in theserum and culture medium.

Accordingly, the invention provides recombinant FGFR fusion proteinsresistant to cleavage and with improved pharmacokinetic profilescompared to the naturally-occurring forms. For example, the inventionprovides FGFR fusion proteins that are more resistant to degradationboth in vitro and in vivo. These FGFR fusion protein constructs may havesingle amino acid changes in the cleavage sites of serum proteases. Theymay also have global deletions of the cleavage sites. These constructscan be made by altering the naturally-occurring sequences using methodsknown to those of skill in the art. The invention also provides FGFRconstructs wherein the junction between the extracellular domains andtransmembrane domains of the receptor are modified to remove proteolyticdegradation sites by methods known to those of skill in the art.

In addition to the deletion mutants described above, the inventionprovides single point mutants, such as substitution mutants resistant toMMP-2 cleavage. Natural substrates of MMP-2 have a preponderance ofproline at the third residue N-terminal to the MMP-2 cleavage site, buthave not been described to have either methionine or glycine residues atthis site. Accordingly, the invention provides for point mutantscorresponding to R1Mut8 (P364M), R1Mut9 (M367N), and R1Mut10 (P364G),such as shown in FIG. 1B, for example. P364M is expected to have asimilar hydrophobicity profile and P364G is expected to have greaterflexibility than wildtype. Also by way of example, the inventionprovides the M367N substitution mutation of the methionine of the MMP-2cleavage site. Asparagine (N) has not been described in any natural orsynthetic MMP-2 substrate, thus its substitution can be expected toattenuate or prevent cleavage by MMP-2. The M367N mutation alsointroduces a potential glycosylation site, namely, NTS into the FGFR1ECD. If this glycosylation site is utilized by the host cell in vitro orin vivo, the N-linked sugars could further shield the FGFR1-IIIb orFGFR1-IIIc extracellular domain from proteolysis. The invention furtherprovides the double variant of FGFR1-IIIb or FGFR1-IIIc, P364G/M367N.Any of the mutants of the invention may, optionally, comprise a linkersequence.

In addition to the deletion and substitution mutants of the FGFR fusionmolecules described above, the invention provides insertion, inversion,and repeat mutants. Some amino acid sequences of FGFR fusion moleculescan be varied without significant effect on the structure or function ofthe protein while others are critical for determining activity.Accordingly, the invention includes variations of the FGFR fusionproteins which show substantial FGFR polypeptide activity and/or whichinclude regions of the FGFR extracellular domains. Mutants of theinvention may have the receptor activity of wild-type FGFR or may haveactivities enhanced or reduced, or broadened with respect to FGF ligandbinding capability, as compared to wildtype. Methods of making thesemutants are generally known in the art.

Variations of the FGFR fusion proteins of the invention can be made andare included herein. Guidance concerning how to make phenotypicallysilent amino acid substitutions is provided by Bowie et al., Science247:1306-1310 (1990). Genetic engineering techniques can be used tointroduce amino acid changes at specific positions of the FGFR fusionprotein and selections, or screens, can be used to identify sequencesthat maintain functionality.

For example, the art cited herein can be followed to produce proteinstolerant of amino acid substitutions. This art indicates which aminoacid changes are likely to be permissive at a certain position of aprotein. For example, most buried amino acid residues require nonpolarside chains, whereas few features of surface side chains are generallyconserved. Typically conservative substitutions of the FGFR fusionproteins are tolerated, such as replacements, one for another, among thealiphatic amino acids Ala, Val, Leu, and Ile; interchange of thehydroxyl residues Ser and Thr, exchange of the acidic residues Asp andGlu, substitution between the amide residues Asn and Gln, exchange ofthe basic residues Lys and Arg, and replacements between the aromaticresidues Phe and Tyr. Substitutions of charged amino acids with othercharged or neutral amino acids may produce proteins with desirableimproved characteristics, such as less aggregation. Aggregation may notonly reduce activity but also be problematic when preparingpharmaceutical formulations, because, for example, aggregates can beimmunogenic (Pinckard et al., Clin. Exp. Immunol. 2:331-340 (1967);Robbins et al., Diabetes 36:838-845 (1987); Cleland et al., Crit. Rev.Therapeutic Drug Carrier Systems, 10:307-377 (1993)). As describedabove, the binding of FGF ligands to FGFRs is both selective andoverlapping. Selected ligands bind to a particular FGFR, but more thanone ligand can bind to a receptor and an FGF ligand may bind to multipleFGFR. Mutating amino acids in the FGFR fusion proteins of the inventioncan change the selectivity of FGF ligand binding to FGFRs.

Transgenic, Knockout, and Other Animals

The invention provides transgenic and knockout animals, respectivelyexpressing exogenous FGFR and lacking endogenous FGFR, as well asanimals injected with the FGFR fusion proteins of the invention or thenucleic acid molecules which encode them. Transgenic animals of theinvention are generally made by expressing an FGFR fusion molecule asdescribed herein with a vector comprising an exogenous promoter and anFGFR extracellular domain and targeting the vector to a predeterminedlocus, wherein the expression pattern of the FGFR fusion transgene isdetermined by the expression pattern of the exogenous promoter. Knockoutmice are generally made by selectively inactivating endogenous FGFR andreplacing it with a mutant allele.

Nonhuman animals of any species, including, but not limited to, mice,rats, rabbits, hamsters, guinea pigs, pigs, micro-pigs, goats, sheep,cows, and non-human primates, for example, baboons, monkeys, andchimpanzees, may be used to generate transgenic and knockout animals. Ina specific embodiment, techniques described herein or otherwise known inthe art, are used to express FGFR fusion molecules of the invention inhumans, as part of a gene therapy protocol.

Any technique known in the art may be used to introduce an FGFRtransgene into animals to produce a founder lines of transgenic animals.Known techniques may also be used to “knock out” endogenous FGFR genes.Techniques for producing transgenic and knockout mice include, but arenot limited to, pronuclear microinjection (Paterson et al., Appl.Microbiol. Biotechnol. 40:691-698 (1994); Carver et al., Biotechnology(NY) 11:1263-1270 (1993); Wright et al., Biotechnology (NY) 9:830-834(1991); and Hoppe et al., U.S. Pat. No. 4,873,191 (1989)); retrovirusmediated gene transfer into germ lines, blastocysts, or embryos (Van derPutten et al., Proc. Natl. Acad. Sci. 82:6148-6152 (1985)); genetargeting in embryonic stem cells (Thompson et al., Cell 56:313-321(1989)); electroporation of cells or embryos (Lo, Mol. Cell. Biol.3:1803-1814 (1983)); introduction of the polynucleotides of theinvention using a gene gun (Ulmer et al., Science 259:1745 (1993));introducing nucleic acid constructs into embryonic pluripotent stemcells and transferring the stem cells back into the blastocyst; andsperm-mediated gene transfer (Lavitrano et al., Cell 57:717-723 (1989).For a review of such techniques, see Gordon, Intl. Rev. Cytol.115:171-229 (1989); U.S. Pat. No. 5,464,764 (Capecchi et al.); U.S. Pat.No. 5,631,153 (Capecchi et al.); U.S. Pat. No. 4,736,866 (Leder et al.);and U.S. Pat. No. 4,873,191 (Wagner et al.). Any technique known in theart may be used to produce transgenic clones containing polynucleotidesof the invention, for example, nuclear transfer into enucleated oocytesof nuclei from cultured embryonic, fetal, or adult cells induced toquiescence (Campbell et al., Nature 380:64-66 (1996); Wilmut et al.,Nature 385:810-813 (1997)).

Gene targeting can be used to integrate the FGFR transgene into thechromosomal site of an endogenous gene. Briefly, vectors comprisingnucleotide sequences homologous to the endogenous gene are designed forthe purpose of integrating, via homologous recombination withchromosomal sequences, into and disrupting the function of thenucleotide sequence of the endogenous gene. The FGFR transgene may alsobe selectively introduced into a particular cell type, thus inactivatingthe endogenous FGFR gene in only that cell type, by following, forexample, the teaching of Gu et al., Science 265:103-106 (1994). Theregulatory sequences required for such a cell-type specific inactivationwill depend upon the particular cell type of interest, and will beapparent to those of skill in the art.

The expression of the recombinant FGFR transgene or knockout allele maybe assayed in the animals of the invention using standard techniques.Initial screening may be accomplished by Southern blot analysis or PCRtechniques to verify that integration of the transgene or null allelehas taken place. The level of mRNA expression of the transgene or nullallele in animal tissues may be assessed using techniques which include,but are not limited to, Northern blot analysis, in situ hybridizationanalysis, and reverse transcriptase-PCR (RT-PCR). Samples of FGFRtransgene-expressing or FGFR null tissue may also be evaluatedimmunocytochemically or immunohistochemically using specific antibodies.

The invention provides transgenic animals which carry an FGFR transgenein all their cells, as well as animals which carry the transgene in someof their cells, such as mosaic or chimeric animals. The transgene may beintegrated as a single transgene or as multiple copies, such as inconcatamers, for example, head-to-head tandems or head-to-tail tandems.An FGFR transgene may also be selectively introduced into and activatedin a particular cell type by following, for example, the teaching ofLasko et al., Proc. Natl. Acad. Sci. 89:6232-6236 (1992)). Theregulatory sequences required for such a cell-type specific activationwill depend upon the particular cell type of interest, and will beapparent to those of skill in the art.

Founder transgenic animals may be bred, inbred, outbred, or crossbred toproduce colonies of a particular animal. Examples of such breedingstrategies include, but are not limited to, outbreeding of founderanimals with more than one integration site in order to establishseparate lines; inbreeding of separate lines in order to producecompound transgenics that express the transgene at higher levels becauseof the effects of additive expression of each transgene; crossingheterozygous transgenic animals to produce animals homozygous for agiven integration site in order to both augment expression and eliminatethe need for screening of animals by DNA analysis; crossing separatehomozygous lines to produce compound heterozygous or homozygous lines;and breeding to place the transgene on a distinct background appropriateto an experimental model of interest.

In an embodiment, the FGFR fusion proteins of the invention areexpressed in transgenic non-human animals produced by the methoddescribed in WO 03/020743. In this method, a cassette including atransgene of interest is targeted to one or more predetermined loci,including loci expressed in most or all cell types. The cassette canfunction as an autonomous unit, directing the expression of thetransgene and optional regulatory or accessory genes in the cassette.The transgene is expressed under the control of the exogenous promoterwithin the cassette. Thus, the expression pattern of the transgene isdetermined by the nature of the exogenous promoter.

Transgenic and knock-out animals of the invention have uses whichinclude, but are not limited to, animal model systems useful inelaborating the biological function of FGFRs, studying conditions and/ordisorders associated with aberrant expression of FGFRs, and in screeningfor compounds effective in modifying or ameliorating these conditionsand/or disorders.

Animals comprising the nucleic acid molecules or the FGFR fusionproteins of the invention are those that have been injected with eitherthe FGFR fusion protein or the nucleic acid construct, such as byhydrodynamic tail vein transfection method, and such as using themini-circle vector construct previously described.

FGFR Fusion Proteins as Decoy Receptor Traps

The FGFR fusion proteins of the invention can function as decoyreceptors for trapping FGF ligands and inhibiting their interaction withFGFR on cell surfaces. Decoy receptors, such as those of the invention,recognize their ligands with high affinity and specificity but arestructurally incapable, of signaling. They compete with wild-typereceptors for ligand binding and participate in ligand/receptorinteractions, thus modulating the activity of or the number offunctioning receptors and/or the cellular activity downstream from thereceptors. Decoy receptors can act as molecular traps for agonistligands and thereby inhibit ligand-induced receptor activation.

Prior to the teachings of the present invention, it was not knownwhether tumors or proliferative cells are dependent on FGF growthfactors in vivo or which FGF ligand may be blocked in order to inhibittumor progression or cell proliferation. Furthermore, it has not beenpreviously reported that the ability to block FGF-induced proliferationcorrelates with lowered levels of FGFR activation.

The FGFR fusion proteins of the invention can be used in combinationwith other decoy receptor traps. Etanercept (Enbrel®) is an example of agenetically engineered decoy receptor trap comprising a fusion proteinof the extracellular ligand-binding domain of the human TNF-α receptorand the Fc region of human IgG1. It acts as a decoy by competitivelyinhibiting TNF-α binding to naturally-occurring TNF-α receptors on thecell-surface, thus inhibiting TNF-α induced proinflammatory activity.Etanercept acts as a cytokine “sponge” and TNF-α antagonist, renderingTNF-α biologically inactive (Goldenberg et al., Clin. Ther. 21:75-87(1999)). It is used to treat rheumatoid arthritis, juvenile rheumatoidarthritis, psoriatic arthritis, and ankylosing spondylitis.

The FGFR fusion proteins of the invention can also be used with a VEGFTrap, which is another example of a soluble recombinant decoy fusionprotein, and is currently in clinical trials. A genetically engineeredfusion protein of one or more extracellular ligand-binding domain of thehuman vascular endothelial growth factor (VEGF) receptor and the Fcregion of human IgG1, the VEGF Trap inhibits angiogenesis by acting as adecoy for naturally-occurring cell surface VEGF receptors. By inhibitingangiogenesis, VEGF decoys can shrink tumors which rely on angiogenesisfor their viability. The biological activity of the decoy trap dependson the portion of the receptor used in the trap. For example, a fusionprotein of the first three Ig domains of the VEGFR1 receptor isoform andthe Fc region of human IgG1 binds to VEGF with an affinity in thepicomolar range and has potent anti-tumorigenic activity but a short invivo half life and significant toxicity (Holash et al., Proc. Natl.Acad. Sci. 99:11,393-11,398 (2002)). VEGF decoy fusion proteins can beengineered to prolong the in vivo pharmacokinetic and pharmacodynamicprofiles, minimize toxicities, and potently inhibit growth andvascularization. Removing a highly basic ten amino acid sequence fromthe third VEGF 1 Ig domain, removing the entire first VEGF 1 Ig domain,and fusing the second Ig domain of VEGFR1 with the third Ig domain ofVEGFR2 have been reported to improve the clinical parameters (Holash etal., Proc. Natl. Acad. Sci. 99:11,393-11,398 (2002)). The combination ofan FGFR fusion protein and the VEGF Trap can be more potent than eitheralone in inhibiting angiogenesis.

The invention provides FGFR decoy receptor trap fusion proteins anddemonstrates that they inhibit the binding of ligands to FGFRs, as shownin greater detail below. The decoy fusion proteins sequester theligands, preventing ligand-receptor binding. The ability of the FGFRreceptor trap fusion proteins to inhibit receptor-ligand binding can bedemonstrated using assays known in the art, for example, competitionELISA assays, as described in more detail below.

The invention provides FGFR decoy receptor traps as therapeutic agents.The FGFR decoy receptor traps of the invention bind to various FGFs,described in more detail herein, which have been demonstrated to beover-expressed in proliferative disease states, compared to normal.These traps can bind FGF ligand with very high affinity, for example,they may bind FGF-2 with a Kd of approximately 15 picomolar.Furthermore, these traps can interfere with FGF signaling in abnormaltissues. The FGFR1-IIIc-Fc and FGFR4-Fc traps of the invention, forexample, can dampen the signaling of FGFR1-IIIc and FGFR4, and perhapsother members of the FGFR family (Zhang et al., J. Biol. Chem. 281:15,694-15,700 (2006)).

Introducing gene trap vectors into embryonic stem cells has producedtransgenic animal lines that reflect the gene expression patterns ofreceptor domains of interest (Coffin et al., Retroviruses Cold SpringHarbor Lab. Press (1997)). Accordingly, the invention provides the useof FGFR gene trap vectors to identify discrete expression patterns ofFGFR genes during signal transduction events associated with normal anddisease states. Constructs with a reporter gene but lacking a promoterare designed so that activation of the reporter gene depends on itsinsertion within an active transcription unit. Integration results in anexpression pattern that reflects the pattern of the endogenoustranscription unit. The reporter gene provides a molecular tag forcloning the “trapped” gene of the transcription unit. Reporter systemswhich can be used with gene trap vectors are known in the art. Followinginsertion, the tagged gene can be detected in space and time by assayingfor the reporter gene product.

Real-Time Detection of Ligand-Receptor Binding

As described herein, FGFs are over-expressed in certain disease states.By acting as decoy receptor traps, FGFR fusion proteins attenuate thebiological activities of the over-expressed FGFs. The profile of FGFswhich bind to a particular FGFR fusion protein in vitro can predict thetherapeutic profile of that fusion protein in vivo. Accordingly, theinvention provides ligand-binding profiles for FGFR fusion proteins ofthe invention and methods of using FGFR fusion molecules of theinvention to treat diseases that over-express FGF ligands.

The invention provides direct ligand-receptor binding measurements bysurface plasmon resonance (SPR) using Biacore technology (Biacore;Piscataway, N.J.), which utilizes biosensor chips to measure bindinginteractions in real time (Dawson et al., Molec. Cell. Biol.25:7734-7742 (2005)). The technology is based on SPR optical phenomenaand detects changes in refractive index that occur close to a sensorchip's surface. One of the interacting components is immobilized on aflexible dextran layer linked to the sensor chip surface, and aninteracting partner flows in solution across the surface. Interactionbetween the two components immobilizes the interacting partner,increasing the mass at the sensor chip surface. The increased massresults in an optical signal, which is recorded in resonance units (RU).One RU represents approximately one picogram of protein bound to thesurface. Biacore technology has been described in U.S. Pat. Nos.6,999,175 B2; 6,808,938 B2; and 5,641,640.

As described in more detail below, FGF ligand binding to fusion proteinsof the invention was measured using the Biacore® X system to measuresurface plasmon resonance (SPR). This method provided a ranking of therelative affinities of FGF ligands for the FGFR fusion proteins of theinvention, for example, FGFR1-IIIc-Fc, R1Mut4, FGFR3-IIIc-Fc, andFGFR4-Fc. Accordingly, the invention provides a method of treating adisease characterized by one or more FGFs which are expressed at ahigher level than normal by administering a binding FGFR fusion proteinof the invention.

Biomarkers of FGFR Fusion Molecule Treatment

Biomarkers can be used to monitor the results of treating subjects withFGFR fusion proteins, including demonstrating efficacy as an end pointin clinical trials. Suitable biomarkers will indicate that an FGF-FGFRsignaling pathway is affected by the FGFR fusion protein. For example,FGF-2 is a suitable biomarker for FGFR1 because a decrease in FGF-2levels in a subject treated with an FGFR1 fusion protein would indicatethat the fusion protein bound FGF-2, sequestered it from active FGFRs,and thus demonstrated treatment efficacy.

Components of the FGFR signaling pathway may also serve as biomarkers todemonstrate treatment efficacy. For example, FGFRs produce intracellularresponses to extracellular ligand binding by intracellular signaling.FGF binding to the extracellular domain of the intact transmembranereceptor activates the catalytic tyrosine kinase domain present on thecytoplasmic portion of the receptor. The ligand induces the FGFR toautophosphorylate a cytoplasmic tyrosine residue, which then serves aspart of a high-affinity binding site for intracellular signalingproteins. One group of these signaling proteins, the extracellularsignal regulated kinases (Erks), also known as mitogen-activated protein(MAP) kinases, become activated when FGFR phosphorylates a threonine anda nearby tyrosine on the Erk protein. Reportedly, ligand binding to cellsurface FGFRs initiate a signal transduction cascade that includes thephosphorylation of Erk to phospho-Erk (pErk). Erk activation thereforeprovides a biomarker for FGFR fusion molecule treatment by providing ameasurement of FGFR intracellular signaling activity, which can bequantified by measuring the phosphorylation of the threonine andtyrosine residues. Erk activation can be determined by methods known inthe art and demonstrated in more detail below. Commercial reagents areavailable that detect Erk immunologically from cell lysates. ELISAand/or Western blot analyses can be performed using these reagents toidentify and measure phosphorylated Erk by methods well-known in theart.

Other biomarkers may also be used to monitor FGFR fusion proteintreatment by providing a measurement of the FGFR signaling pathway. Forexample, a reduction in phosphorylated FGFR (pFGFR), or a reduction ofthe basal phosphorylation level of fibroblast growth factor receptorsubstrate 2 (pFRS2) and/or dual specificity phosphatase (DSP) wouldindicate efficacious treatment with FGFR fusion proteins.

FGFR Fusion Proteins Inhibit the Viability and/or Proliferation ofProliferative Cells

Proliferative cells often depend on extracellular signaling by growthfactors for their survival and growth. The FGFR fusion proteins of theinvention can inhibit the viability and/or the proliferation of cancercells and other proliferative cells both in vitro and in vivo.Accordingly, the invention provides methods of inhibiting viabilityand/or proliferation of proliferative cells, methods of inhibitingangiogenesis, and methods of treating cancer in a subject by providingan FGFR fusion protein, as described herein, and administering thefusion protein to the subject. The effect of FGFR fusion proteins oncell viability and/or proliferation in vitro was examined on culturedtumor cells and their effects on tumor cell viability and proliferationin vivo was examined in an animal tumor model.

The CellTiter-Glo™ Luminescent Cell Viability Assay (Promega; Madison,Wis.), which was designed to measure the number of viable cells inculture (Sussman et al., Drug Disc. Dev. 5:71-71 (2002), was used hereinto determine cell viability and proliferation. Cellular adenosinetriphosphate (ATP) levels indicate cell viability; ATP levels droprapidly when the cell loses viability. The assay uses a stable form offirefly luciferase to measure ATP as an indicator of metabolicallyactive, i.e., viable, cells. The luciferase converts beetle luciferin toluciferin oxide in the presence of ATP, magnesium, and oxygen. Theresulting luminescent signal is proportional to the number of viablecells present in the culture and can be detected with a luminometer orCCD camera. Because the signal is proportional to cell number, itmeasures both viability and proliferation. Under stated media and serumconditions, the assay is linear over a wide range of cell numbers.

The invention provides methods of using the FGFR fusion proteins of theinvention to inhibit the viability and/or proliferation of multipleproliferative cell types, whether dysplastic cells, premalignant cellsor malignant tumor cells; methods to inhibit the viability and/orproliferation of other cell types, such as endothelial cells; andmethods to inhibit angiogenesis, in vitro, ex vivo, or in vivo. Asdescribed in more detail below, FGFR fusion proteins of the inventioncan be used to inhibit a wide variety of cancer cell types, includinglung, kidney, brain, breast, liver, ovarian, prostate, and/or colorectalcancer cells, for example. The FGFR fusion proteins of the inventioneach have different specificities to different cancer cell types, asshown in greater detail below, and can be used to treat different tumortypes depending on such specificities.

For example, the FGFR fusion proteins of the invention, such asFGFR1-IIIc-Fc fusion proteins, can be used to inhibit the viabilityand/or proliferation of malignant human glioma cells (for example, U251cells); malignant human brain cancer cells (for example, SF268 cells);human lung cancer cells (for example, A549 cells); malignant lungnon-squamous carcinoma cells (for example, NCI-H522 and NCI-H226 cells);malignant glioblastoma cells (for example, U118 and WT111 cells); andmalignant kidney cells (for example, Caki-1 cells).

The invention also provides methods for using FGFR fusion proteins ofthe invention to inhibit the proliferation of tumor cells and otherproliferative cells, such as endothelial cells, in vivo. This in vivoactivity can be demonstrated by administering the FGFR fusion protein ofthe invention to inhibit in vivo formation of tumors in animal xenograftmodels. As shown herein, FGFR1-IIIc-Fc effectively inhibited tumorgrowth in this model. Accordingly, the invention provides a method ofinhibiting tumor growth and tumor cell proliferation in a subject byproviding a composition comprising an FGFR fusion protein of theinvention and administering the composition to the subject.

The invention provides methods of inhibiting viability and/orproliferation of proliferative cells, such as endothelial cells, underconditions in which the proliferation of such cells is not desirable.For example, macular degeneration and tumor angiogenesis are conditionsunder which excess growth of blood vessels, thus endothelial cells, isundesirable. Accordingly, the invention further provides methods ofinhibiting angiogenesis by administering the FGFR fusion proteins of theinvention to a subject in need of such treatment. As described ingreater detail below, dosing schedules and dosing routes are generallyknown in the art; the latter may include intravenous, subcutaneous,intraperitoneal, and oral administration.

FGF and FGFR Expression in Human Cancers

Gene amplification is among the mechanisms of oncogene activation thatcan lead to specific types of cancers. The invention provides ananalysis of the gene expression profile of breast cancer tissuesresiding in the proprietary GeneLogic database, and the finding that theFGFR1 gene was amplified in 10-15% of breast cancer patients. Asdescribed herein, such gene amplification has implications for tumorcell growth and/or survival, thus interrupting signaling between an FGFRand an FGF ligand is a useful approach to inhibiting tumor growth.

The invention also provides further analysis of the expression profilesof different tumor types resident in the proprietary GeneLogic databasefor FGF and FGFR expression, and the finding that certain tumorsexpressed a higher level of FGFR1, FGFR3, and/or FGFR4. The inventionfurther provides that certain tumors expressed a higher level of certainFGF ligands, implicating active FGF/FGFR signaling pathways inmaintaining the viability and/or proliferative capacity of the cancercells or the endothelial cells feeding the cancer cells. Informationrelating to the tumor types that over-express an FGFR and/or an FGF isprovided in the tables below.

Accordingly, the invention provides methods and compositions for FGFRfusion proteins which are suitable for use in treating proliferativediseases characterized by over-expression of an FGFR, FGF, or both. Theanalysis performed herein and described in greater detail in theExamples, provides the FGFR and FGF gene expression profiles of varioushyperproliferative tissues. Thus, the over-expression of the FGFRs andtheir ligands are correlated with particular disease states. The FGFRfusion proteins of the invention are efficacious in treating thediseases in which the FGFR component, or its ligand, is over-expressed.

Therapeutic Compositions and Formulations

Routes of Administration and Carriers

The FGFR fusion molecules of the invention can be administered in vivoby a variety of routes, including intravenous, intra-arterial,subcutaneous, parenteral, intranasal, intramuscular, intracardiac,intraventricular, intratracheal, buccal, rectal, intraperitoneal,intradermal, topical, transdermal, and intrathecal, or otherwise byimplantation or inhalation. They may be administered in formulations, asdescribed in more detail below. They may be administered in powder formintranasally or by inhalation. They may be administered assuppositories, for example, as formulated by mixing with a variety ofbases, such as emulsifying bases, water-soluble bases, cocoa butter,carbowaxes, and polyethylene glycols; which melt at body temperature,yet are solidified at room temperature. Jet injection can be used forintramuscular or intradermal administration (Furth et al., Anal.Biochem. 205:365-368 (1992)). The DNA can be coated onto goldmicroparticles and delivered intradermally by a particle bombardmentdevice, or “gene gun” as described in the literature (Tang et al.,Nature 356:152-154 (1992)), where gold microprojectiles are coated withthe DNA, then bombarded into skin cells. These methods of in vivoadministration are known in the art.

In some embodiments, fusion molecule compositions are provided informulation with pharmaceutically acceptable carriers, a wide variety ofwhich are known in the art (Gennaro, Remington: The Science and Practiceof Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th ed. (2003);Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems,7^(th) ed., Lippencott Williams and Wilkins (2004); Kibbe et al.,Handbook of Pharmaceutical Excipients, 3^(rd) ed., Pharmaceutical Press(2000)). Pharmaceutically acceptable carriers, such as vehicles,adjuvants, carriers, or diluents, are available to the public. Moreover,pharmaceutically acceptable auxiliary substances, such as pH adjustingand buffering agents, tonicity adjusting agents, stabilizers, wettingagents and the like, are available to the public.

The fusion molecules of the invention may be employed in combinationwith a suitable pharmaceutical carrier to comprise a pharmaceuticalcomposition for parenteral administration. Accordingly, the inventionprovides a composition comprising an FGFR fusion molecule of theinvention and a pharmaceutically acceptable carrier. Such compositionscomprise a therapeutically effective amount of the polypeptide, agonist,or antagonist and a pharmaceutically acceptable carrier. Such a carrierincludes, but is not limited to, saline, buffered saline, dextrose,water, glycerol, ethanol, and combinations thereof. The formulationshould suit the mode of administration.

In pharmaceutical dosage, the FGFR fusion molecule compositions can beadministered in the form of their pharmaceutically acceptable salts,either alone or in appropriate association or combination with otherpharmaceutically active compounds. The FGFR fusion molecule compositionsare formulated in accordance with the mode of administration. Thus, thesubject compositions can be formulated into preparations in solid,semi-solid, liquid, or gaseous forms, such as tablets, capsules,powders, granules, ointments, solutions, suppositories, enemas,injections, inhalants, and aerosols. The methods and excipients citedherein are merely exemplary and are in no way limiting.

The agents, polynucleotides, and polypeptides can be formulated intopreparations for injection by dissolving, suspending, or emulsifyingthem in an aqueous or nonaqueous solvent, such as vegetable or othersimilar oils, synthetic aliphatic acid glycerides, esters of higheraliphatic acids or propylene glycol; and if desired, with conventionaladditives such as solubilizers, isotonic agents, suspending agents,emulsifying agents, stabilizers and preservatives. They may beformulated into preparations for administration via inhalation, forexample as formulated into pressurized acceptable propellants such asdichlorodifluoromethane, propane, nitrogen, and the like. The FGFRfusion proteins of the invention can be formulated into a sustainedrelease microcapsules, such as with biodegradable or non-biodegradablepolymers, using techniques known in the art. An example of abiodegradable formulation suitable for use herein includes poly lacticacid-glycolic acid polymer. An example of a non-biodegradableformulation suitable for use herein includes a polyglycerin fatty acidester. A method of making these formulations is described in, forexample, EP 1 125 584 A1. Other formulations for parenteral delivery canalso be used, as conventional in the art.

The FGFR fusion molecule compositions will be formulated and dosed in afashion consistent with good medical practice, taking into account theclinical condition of the individual subject, the site of delivery ofthe fusion molecule composition, the method of administration, thescheduling of administration, and other factors known to practitioners.The effective amount of FGFR fusion molecule for purposes herein is thusdetermined by such considerations.

The invention also provides a pharmaceutical pack or kit comprising oneor more containers filled with one or more of effective doses of thepharmaceutical FGFR fusion protein compositions of the invention.Associated with such container(s) can be a notice in the form prescribedby a governmental agency regulating the manufacture, use, or sale ofpharmaceuticals or biological products. Such a notice reflects theagency's approval for manufacture, use, or sale for humanadministration. In addition, the FGFR fusion molecules of the inventionmay be employed in conjunction with other therapeutic agents.

Unit dosage forms can be provided wherein each dosage unit contains apredetermined amount of the composition containing one or more agents.In an embodiment, an FGFR fusion molecule composition is supplied insingle-use prefilled syringes for injection. The composition maycomprise saline, sucrose, or the like; a buffer, such as phosphate, orthe like; and be formulated within a stable and effective pH range. Inan embodiment, an FGFR fusion molecule composition is provided as alyophilized powder in a multiple-use vial, which can be reconstitutedupon addition of an appropriate liquid, for example, sterilebacteriostatic water. In an embodiment, an FGFR fusion moleculecomposition comprises one or more substances that inhibit proteinaggregation, including, but not limited to, sucrose or arginine. In anembodiment, a composition of the invention comprises heparin and/or aproteoglycan.

These pharmaceutical compositions are administered in an amounteffective for treatment and/or prophylaxis of the specific indication.The effective amount is typically dependent on the weight of the subjectbeing treated, his or her physical or health condition, theextensiveness of the condition to be treated, and/or the age of thesubject being treated. In general, the FGFR fusion proteins of theinvention are to be administered in an amount in the range of about 5ug/kg body weight to about 10 mg/kg body weight per dose. Optionally,the FGFR fusion proteins of the invention can be administered in anamount in the range of about 10 ug/kg body weight to about 9 mg/kg bodyweight per dose. Further optionally, the FGFR fusion proteins of theinvention can be administered in an amount in the range of about 100ug/kg body weight to about 8 mg/kg body weight per dose. Stilloptionally, the FGFR fusion proteins of the invention can beadministered in an amount in the range of about 1 mg/kg body weight toabout 7 mg/kg body weight per dose.

The FGFR fusion protein compositions can be administered as needed tosubjects in need of inhibition of FGF ligand/FGFR signaling pathway.Determination of the frequency of administration can be made by personsskilled in the art, such as an attending physician based onconsiderations of the condition being treated, age of the subject beingtreated, severity of the condition being treated, general state ofhealth of the subject being treated and the like. In one embodiment, aneffective dose of the FGFR fusion protein is administered to a subjectone or more times. In one embodiment, the FGFR fusion protein of theinvention is administered to the subject at least twice a week for atleast a week. In another embodiment, the FGFR fusion protein isadministered at least three times a week for at least one week. In afurther embodiment, the FGFR fusion protein is administered to thesubject for at least two weeks. In yet another embodiment, the FGFRfusion protein of the invention is administered to the subject for atleast three weeks. Administration of the FGFR fusion protein can becontinuously for at least two or three weeks or can be non-continuous,such as taking a one or two week break from treatment and resumingtreatment after such break.

Combination Therapy

FGFR fusion molecules of the invention may be administered alone or withother modes of treatment. They may be provided before, substantiallycontemporaneous with, or after other modes of treatment, for example,surgery, chemotherapy, radiation therapy, or the administration of abiologic, such as a therapeutic antibody. Accordingly, the inventionprovides a method of combining treatment which blocks the signalingpathways utilized by fibroblast growth factors and receptors withtreatment which blocks the signaling pathways utilized by other growthfactors, which can be expected to be more effective in patients withtumors that express FGFs and/or FGFRs, as well as other growth factorsand/or their receptors. This therapeutic approach can be applied torapidly growing tumors and highly vascularized tumors, for example,glioblastomas. FGFR fusion molecules of the invention can be used incombination with fusion molecules of other growth factor receptors. Forexample, the FGFR fusion protein of the invention can be combined with asoluble VEGFR to inhibit tumor growth and/or to inhibit angiogenesis intumors.

Further, the invention provides combination therapy that blocks the FGFand other signaling pathways such as PDGF, VEGF, and/or EGF signalingpathways. The FGFR fusion molecules of the invention can be used in suchcombination therapy. One or more of the agents that inhibit PDGFR-alpha,PDGFR-beta, VEGFR, and/or EGF receptors can be combined with FGFR fusionproteins of the invention for therapeutic use. The compositions thatblock the FGF signaling pathways may be provided simultaneously or maybe provided sequentially in any order with compositions that block thePDGF, VEGF, and/or EGF signaling pathways. Combination therapy mayinclude the use of fusion proteins comprising the extracellular domainsof PDGFR-alpha, PDGFR-beta, VEGFR, EGFR, and the FGFR fusion proteins ofthe invention.

Uses of FGFR Fusion Molecules

FGFR fusion molecules of the invention, and fragments and variantsthereof, may be used to diagnose, provide a prognosis for, prevent,treat, and develop treatments for disorders mediated, either directly orindirectly, by hyperactive or excess FGF ligand or FGFR. FGFR fusionmolecules of the invention, and fragments and variants thereof, may beadministered to a patient at risk for or suffering from such a disorder.

Accordingly, the invention provides a method of diagnosing a diseasecharacterized by the over-expression of one or more FGF and/or FGFR, ora fragment or variant thereof, by measuring the real-time receptorligand binding of one or more FGF to one or more FGFR. The method can beperformed, for example, by providing a biological specimen from asubject, and measuring the binding of an FGF ligand or FGFR in thespecimen to one or more cognate FGFR or FGF ligands. The results of thebinding measurements can be used to diagnose the presence or absence ofa disease characterized by the over-expression of the FGF(s) or FGFR(s).

The invention also provides a method of treating a condition in asubject comprising providing a composition comprising an FGFR fusionmolecule of the invention and administering the composition to thesubject, wherein the condition comprises a proliferative disease,including cancers and disorders of angiogenesis. The FGFR fusionmolecules of the invention are useful for inhibiting cancer cellproliferation and/or viability. The FGFR fusion molecules of theinvention can be used accordingly in a variety of settings for thetreatment of animal, including human, cancers.

The FGFR fusion molecules of the invention can be used to treat,modulate, or prevent malignant, pre-malignant, and benign tumors. Forexample, they can treat metastasizing or non-metastasizing malignanttumors, which are typically at an advanced stage of tumor development,and may be life threatening. They can also be used to treatpre-malignant tumors, which are typically at a more advanced stage oftumor development than benign tumors, but have not progressed tomalignancy. They can further be used to treat benign tumors, whichtypically show some abnormal cell characteristics and are at an earlystage in tumor development. The benign tumor may or may not progress toa pre-malignant or malignant tumor. The FGFR fusion molecules of theinvention can be used to treat solid tumors formed by a collection ofcells typically localized in a tissue or organ, for example, sarcomasand carcinomas such as, but not limited to fibrosarcomas, myxosarcomas,liposarcomas, chondrosarcomas, osteogenic sarcomas, chordomas,angiosarcomas, endotheliosarcomas, lymphangiosarcomas,lymphangioendotheliosarcomas, synoviomas, mesotheliomas, Ewing's tumors,leiomyosarcomas, rhabdomyosarcomas, colon carcinomas, colorectalcancers, gastic cancers, pancreatic cancers, breast cancers, ovariancancers, prostate cancers, squamous cell carcinomas, basal cellcarcinomas, adenocarcinomas, sweat gland carcinomas, sebaceous glandcarcinomas, papillary carcinomas, papillary adenocarcinomas,cystadenocarcinomas, medullary carcinomas, bronchogenic carcinomas,renal cell carcinomas, hepatomas, liver metastases, bile ductcarcinomas, choriocarcinomas, seminomas, embryonal carcinomas, thyroidcarcinomas such as anaplastic thyroid cancers, Wilms' tumors, cervicalcancers, testicular tumors, lung carcinomas such as small cell lungcarcinomas and non-small cell lung carcinomas, bladder carcinomas,epithelial carcinomas, gliomas, astrocytomas, medulloblastomas,craniopharyngiomas, ependymomas, pinealomas, hemangioblastomas, acousticneuromas, oligodendrogliomas, meningiomas, melanomas, neuroblastomas,and retinoblastomas. Also among the cancers within the scope of theinvention are hematologic malignancies, breast cancer, such asinfiltrating ductal carcinoma and adenocarcinoma; lung cancer, such assquamous cell carcinoma, non-small cell lung cancer, and lungadenocarcinoma; prostate cancer; bladder cancer; pancreatic cancer;ovarian cancer, salivary cancer; pituitary cancer; renal cell carcinoma;melanoma; glioblastoma; retinoblastoma; and/or cancer metastases inbone, including bone metastasis from prostate cancer.

Tumors comprising dysproliferative changes, such as hyperplasias,metaplasias, and dysplasias, can be treated, modulated, or preventedwith the present invention as well, such as those found in epithelialtissues, including the cervix, esophagus, and lung, for example.Hyperplasia is a form of controlled cell proliferation involving anincrease in cell number in a tissue or organ, without significantalteration in structure or function. By way of example, endometrialhyperplasia often precedes endometrial cancer. Metaplasia is a form ofcontrolled cell growth in which one type of adult or fullydifferentiated cell substitutes for another type of adult cell.Metaplasia can occur in epithelial or connective tissue cells. Atypicalmetaplasia involves a somewhat disorderly metaplastic epithelium.Dysplasia is frequently a forerunner of cancer, and is found mainly inthe epithelia; it is a disorderly form of non-neoplastic cell growth,involving losses in individual cell uniformity and in the cell'sarchitectural orientation. Dysplasia characteristically occurs wherethere exists chronic irritation or inflammation and is often found inthe cervix, respiratory passages, oral cavity, and gall bladder. Otherexamples of benign tumors which can be treated, modulated or preventedin accordance with the present invention include arteriovenous (AV)malformations, particularly in intracranial sites and myoleomas.

The FGFR fusion molecules of the invention, or variants or fragmentsthereof, can be used to treat cancer patients sensitive to the effectsof FGFR signaling. They are useful in a subset of patients thatover-express FGFR1 and/or FGF-2, for example, subsets of patients withbreast cancer, lung cancer, kidney cancer, prostate cancer, andglioblastoma. Treatment effectiveness can be assessed, for example, bymeasuring the patient's level of a biomarker, for example, FGF-2, pFGFR,DSP, and/or pFRS2 (Guddo et al., Hum. Pathol. 30:788-794 (1999)), asdescribed above.

The invention also provides compositions and methods for treatingglioblastoma, a rapidly growing and highly vascularized tumor.Platelet-derived growth factor (PDGF) is expressed at high levels inmany human glioblastomas. Further, in addition to their role inpromoting tumor cell growth and survival, FGFs are potent angiogenicfactors which may be expected to promote the growth of highly vasculartumors, such as glioblastomas. Blocking the effects of PDGF on cellgrowth or survival together with blocking the FGF signaling pathway withthe FGFR fusion protein of the invention may thus retard the progressionof glioblastoma development.

FGF-2 and FGFR1 are expressed in the tumor cells and thetumor-associated stromal cells and vessels of patients with non-smallcell lung cancer. The FGFR fusion proteins of the invention, such asFGFR1-IIIc-Fc or R1Mut4, for example, can be administered to suchpatients to block growth stimulation by FGF-2 binding to FGFR1 andinhibit tumor growth.

Stromal-epithelial interactions are important determinants of malignantvs. benign prostatic growth (Conte et al., Int. J. Cancer 107:1-10(2003)). Prostate cancer, and also breast cancer, kidney cancer, andmultiple myeloma, tend to metastasize to the bone. While breast cancerbone metastases tend to form lytic bone lesions, prostate cancermetastases tend to form blastic lesions characterized by an excess ofabnormally dense bone. Further interaction of prostate cancer metastaseswith the local bone environment may then alter normal bone homeostasis,shifting it toward an osteoblastic phenotype. Kidney metastases mayexhibit both lytic and blastic bone lesions.

Since FGFs contribute to normal bone formation and are expressed locallyin the bone stromal environment, they may play a role in seeding,growth, and survival of prostate cancer bone metastases. FGFs have beenimplicated in bone formation, affecting osteoprogenitor cellreplication, osteoblast differentiation, and apoptosis. Thus, agentswhich block FGF/FGFR interactions, including FGFR fusion molecules ofthe invention, or variants or fragments thereof, can be used to treatbone metastases in prostate cancer. Such agents will not only inhibitlocal osteoblastic conversion events, but also inhibit initial seeding,growth, and survival of prostate cancer bone metastases.

The invention also provides methods of using FGFR fusion proteins of theinvention, or variants or fragments thereof, to inhibit angiogenesis,for example, in tumorigenesis and macular degeneration. By way ofexample, fusion proteins comprising FGFR1-IIIc and/or FGFR4 may be usedto bind undesirable proangiogenic FGFs and decrease angiogenesis. Usefulcompositions include those comprising fusion molecules comprising thefusion proteins of the invention as described herein, including thosewith Fc fusion partners.

The invention provides methods of treating cancers resistant to othercancer therapeutic agents. For example, the FGFR fusion proteins of theinvention can be used to treat cancers resistant to ErbB oncogeneinhibitors, such as Herceptin®. They are also useful in treating cancersresistant to inhibitors of VEGF, such as Avastin®.

The FGFR fusion proteins and the polynucleotide molecules that encodethem are useful in treating proliferative diseases and diseasesinvolving angiogenesis, including cancer. They can be used to diagnose,prevent, and treat these diseases.

With respect to ranges of values, the invention encompasses eachintervening value between the upper and lower limits of the range to atleast a tenth of the lower limit's unit, unless the context clearlyindicates otherwise. Further, the invention encompasses any other statedintervening values. Moreover, the invention also encompasses rangesincluding either or both of the upper and lower limits of the range,unless specifically excluded from the stated range.

Unless defined otherwise, the meanings of all technical and scientificterms used herein are those commonly understood by one of skill in theart to which this invention belongs. One of skill in the art will alsoappreciate that any methods and materials similar or equivalent to thosedescribed herein can also be used to practice or test the invention.

It must be noted that, as used herein and in the appended claims, thesingular forms “a,” “or,” and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “asubject polypeptide” includes a plurality of such polypeptides andreference to “the agent” includes reference to one or more agents andequivalents thereof known to those skilled in the art, and so forth.

Further, all numbers expressing quantities of ingredients, reactionconditions, % purity, polypeptide and polynucleotide lengths, and soforth, used in the specification and claims, are modified by the term“about,” unless otherwise indicated. Accordingly, the numericalparameters set forth in the specification and claims are approximationsthat may vary depending upon the desired properties of the presentinvention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits, applying ordinary roundingtechniques. Nonetheless, the numerical values set forth in the specificexamples are reported as precisely as possible. Any numerical value,however, inherently contains certain errors from the standard deviationof its experimental measurement.

The specification is most thoroughly understood in light of thereferences cited herein. Each of these references is hereby incorporatedby the reference in its entirety.

EXEMPLARY MODES FOR CARRYING OUT THE INVENTION

The examples, which are intended to be purely exemplary of the inventionand should therefore not be considered to limit the invention in anyway, also describe and detail aspects and embodiments of the inventiondiscussed above. The examples are not intended to represent that theexperiments below are all or the only experiments performed. Effortshave been made to ensure accuracy with respect to numbers used (forexample, amounts, temperature, etc.) but some experimental errors anddeviations should be accounted for. Unless indicated otherwise, partsare parts by weight, molecular weight is weight average molecularweight, temperature is in degrees Centigrade, and pressure is at or nearatmospheric.

Example 1 Sequence Alignment of Partial IgIII Domains and the MembraneProximal Regions of FGFRs and FGFR Variants

FIG. 1A shows an alignment of the amino acid sequences of a part of theIgIII domain of each of the seven FGFR family members, FGFR1-IIIb,FGFR1-IIIc, FGFR2-IIIb, FGFR2-IIIc, FGFR3-IIIb, FGFR3-IIIc, and FGFR4,using the Clustal W version 1.8 program of the European MolecularBiology Laboratory (EMBL) bioinformatics search site.

FIG. 1A also illustrates the organization of the parental FGFR1-IIIc-Fcfusion protein (nucleotide SEQ ID NO: 4, protein SEQ ID NO: 95) andcorresponding mutants. The IgIII domain is followed by the C-terminalportion of the ECD, which is followed by the Fc portion of an antibody.The alignment marks the truncation locations of the R1Mut1 (nucleotideSEQ ID NO: 6, protein SEQ ID NO: 97), R1Mut2 (nucleotide SEQ ID NO: 7,protein SEQ ID NO: 98), R1Mut3 (nucleotide SEQ ID NO: 8, protein SEQ IDNO: 99), R1Mut4 (nucleotide SEQ ID NO: 9, protein SEQ ID NO: 100), andR1Mut5 (nucleotide SEQ ID NO: 10, protein SEQ ID NO: 101) variants ofFGFR1-IIIc and the position of an Fc portion of an IgG antibody. R1Mut1,R1Mut2, R1Mut3, R1Mut4, and R1Mut5 also had the linker encoding aminoacids “GS” removed from between the FGFR1-IIIc and Fc domains.

FIG. 1B illustrates additional variants from the parental FGFR1-IIIc-Fc,which were also made and used in the invention. The variants shown inFIG. 1B all had the linker GS removed. The variant R1Mut6 (nucleotideSEQ ID NO: 5, protein SEQ ID NO: 96), had only the GS linker deleted.Another variant, R1Mut7 (nucleotide SEQ ID NO: 11, protein SEQ ID NO:102), had a deletion of amino acid residues PA. The variant R1Mut8(nucleotide SEQ ID NO: 12, protein SEQ ID NO: 103), had an amino acidsubstitution P364M, in which the proline residue was substituted withmethionine. The variant R1Mut9 (nucleotide SEQ ID NO: 13, protein SEQ IDNO: 104) had an amino acid substitution M367N, in which the methionineresidue was substituted with asparagine. The variant R1Mut10 (nucleotideSEQ ID NO: 44, protein SEQ ID NO: 135) had an amino acid substitutionP364G, in which the proline residue was substituted with glycine.

FIG. 2 shows an alignment of the amino acid sequences of a part of theIgIII domain of each of the seven FGFR family members, using the ClustalW version 1.8 program of EMBL (European Molecular Biology Laboratory)bioinformatics search site. FIG. 2 illustrates the organization of theFGFR4-Fc fusion protein (nucleotide SEQ ID NO: 65, protein SEQ ID NO:156) and corresponding mutants. The alignment marks the truncationlocations of the R4Mut1 (nucleotide SEQ ID NO: 71, protein SEQ ID NO:162), R4Mut2 (nucleotide SEQ ID NO: 72, protein SEQ ID NO: 163), R4Mut3(nucleotide SEQ ID NO: 73, protein SEQ ID NO: 164), R4Mut4 (nucleotideSEQ ID NO: 74, protein SEQ ID NO: 165), R4Mut5 (nucleotide SEQ ID NO:75, protein SEQ ID NO: 166) and R4Mut6 (nucleotide SEQ ID NO: 66,protein SEQ ID NO: 157) variants of FGFR4. FIG. 2 also indicates theposition of an Fc portion of an IgG antibody. R4Mut1, R4Mut2, R4Mut3,R4Mut4, R4Mut5, and R4Mut6 also had the linker encoding amino acids ‘GS’removed from between the FGFR4 and Fc domains.

Example 2 Expression of FGFR Fusion Proteins

The fusion proteins of the invention were expressed in 293-6E host cellsusing the pTT5 vector (Biotechnology Research Institute; Montreal,Canada) transfected into 293-6E cells (Biotechnology Research Institute;Montreal, Canada), which were then cultured to produce the fusionproteins. An expression vector that comprised the cDNA of FGFR1-IIIc-Fc(SEQ ID NO: 4), encoding the extracellular domain of human FGFR1-IIIc(SEQ ID NO: 1) was constructed from an open-reading frame cDNA libraryprepared internally. This cDNA was linked at its C-terminus through alinker encoding the amino acids GS to cDNA encoding an Fc fragment ofhuman IgG1 heavy chain (SEQ ID NO: 80) to produce a fusion constructhereafter referenced as “FGFR1-IIIc-Fc cDNA” and the expression productthereof as “FGFR1-IIIc-Fc protein.” The Fc fragment was also obtainedfrom an open-reading frame cDNA library prepared internally. This cDNAfusion construct was inserted into a pTT5 vector by conventionaltechniques to produce the FGFR1-IIIc-Fc/pTT5 expression vector.

Expression constructs for expressing the FGFR3-IIIc-Fc (nucleotide SEQID NO: 85, protein SEQ ID NO: 176) and FGFR4-Fc fusion proteins in293-6E host cells using the pTT5 vector were made in a manner similar tothat described above using cDNAs prepared internally and conventionaltechniques. Similar expression constructs for expressing FGFR variants,such as R1Mut1, R1Mut2, R1Mut3, R1Mut4, R1Mut5, R1Mut6 (GS deletion),R1Mut7 (PA deletion), R1Mut8 (P364M), R1Mut9 (M367N), R4Mut1, R4Mut2,R4Mut3, R4Mut4, R4Mut5, and R4Mut6 (GS deletion) using the pTT5 vectorwere each made from the FGFR1-IIIc-Fc cDNA using PCR and conventionalmutagenesis techniques.

The variants R1Mut1, R1Mut2, R1Mut3, R1Mut4, and R1Mut5, produced inthis manner, each contained the same amino acid sequence as the parentFGFR1-IIIc-Fc fusion protein (protein SEQ ID NO: 95) except for thedeletion of the linker amino acids GS and also certain amino acidresidues at the C-terminus of the wildtype FGFR1-IIIc extracellulardomain, as described in Example 1. R1Mut1 comprised an amino acidsequence ending with amino acid residues MTSP immediately preceding theFc fragment. R1Mut2 comprised an amino acid sequence ending with aminoacid residues RPAV immediately preceding the Fc fragment. R1Mut3comprised an amino acid sequence ending with amino acid residues ERPAimmediately preceding the Fc fragment. R1Mut4 comprised an amino acidsequence ending with amino acid residues LEAL immediately preceding theFc fragment. R1Mut5 comprised an amino acid sequence ending with aminoacid residues AWLT immediately preceding the Fc fragment. The variantsR1Mut6, R1Mut7, R1Mut8, and R1Mut9, also produced in this manner, eachcontained the same amino acid sequence as the parent FGFR1-IIIc-Fc thelinker GS removed.

The variants R4Mut1, R4Mut2, R4Mut3, R4Mut4, R4Mut5, and R4Mut6, whichwere described in Example 1, were also produced from 293-6E host cellsusing the pTT5 vector in the manner described for FGFR1-IIIc-Fc and theR1 mutants. R4Mut1 comprised an amino acid sequence ending with aminoacid residues AAPE immediately preceding the Fc fragment. R4Mut2comprised an amino acid sequence ending with amino acid residues PTWTimmediately preceding the Fc fragment. R4Mut3 comprised an amino acidsequence ending with amino acid residues LPEE immediately preceding theFc fragment. R4Mut4 comprised an amino acid sequence ending with aminoacid residues TVLP immediately preceding the Fc fragment. R4Mut5comprised an amino acid sequence ending with amino acid residues LTVLimmediately preceding the Fc fragment. R4Mut6 comprised an amino acidsequence ending with amino acid residues RYTD immediately preceding theFc fragment.

The host cell line CHO-S can, in certain embodiments, producerecombinant proteins with higher yields and/or different glycosylationpatterns than the 293-6E host cell line. Fusion proteins of theinvention were expressed in CHO-S host cells with the vector pcDNA3.1(Invitrogen; Carlsbad, Calif.). The expression vectors were transfectedinto the CHO-S host cells (Invitrogen; Carlsbad, Calif.), which werethen cultured to produce the fusion proteins. The FGFR1-IIIc-Fc cDNA wassubcloned into the pcDNA3.1 vector using PCR and conventional subcloningtechniques. Expression constructs for expressing FGFR3-IIIc-Fc andFGFR4-Fc fusion proteins in CHO-S host cells using the pcDNA3.1 vectorwere made in a manner similar to that described above, using PCR andconventional subcloning techniques.

Similar expression constructs for expressing the FGFR4-Fc variantsR4Mut1, R4Mut2, R4Mut3, R4Mut4, R4Mut5, and R4Mut6 in CHO-S host cellsusing the pcDNA3.1 vector was made from the FGFR4-Fc cDNA using PCR andconventional subcloning techniques. Expression vectors for other FGFR-Fcfusion proteins and variants can also be made in a similar manner andthe fusion proteins expressed as discussed herein using methods known inthe art.

DG44 is a cell line derivative of the CHO-S cell line and can, in someembodiments, produce higher yields of recombinant proteins than CHO-Scells. The fusion proteins of the invention were expressed in DG44 hostcells (Invitrogen; Carlsbad, Calif.) using the pDEF38 vector (ICOSCorporation; Bothell, Wash.) transfected into DG44 cells as host cells,which were then cultured to produce the fusion proteins. For example,FGFR1-IIIc-Fc cDNA was subcloned into the pDEF38 vector using PCR andconventional subcloning techniques.

A similar expression construct for expressing the FGFR1-IIIc-Fc variantR1Mut4 in DG44 host cells using the pDEF38 vector was made using PCR andconventional subcloning techniques. Expression vectors for other FGFR-Fcfusion proteins and variants, for example, FGFR3-IIIc-Fc and FGFR4-Fc,can also be made in a similar manner and fusion proteins expressed asdiscussed herein.

Long-term expression of fusion proteins in mice using a mini-circlevector with the fusion constructs, was performed as described in Chen etal., Hum. Gene Ther. 16:126-131 (2005); Rui, E. et al., Hum. Gene Ther.16:558-570 (2005); and WO 04/020605, using a parent vector obtained fromDr. Mark Kay at Stanford University (Stanford, Calif.). This parentvector contained an alpha1-antitrypsin promoter, an apoE enhancer, ahuman factor IX intron, and a bovine polyA sequence. The parent vectorwas modified by inserting the FGFR1-IIIc-Fc, FGFR4-Fc, or R1Mut4 cDNA asthe gene of interest, placing such cDNA immediately after the humanFactor IX intron in the parent vector using PCR and conventionalsubcloning techniques. Similar expression vectors for other FGFR-Fcfusion proteins, including FGFR3-IIIc-Fc and the variants describedherein, can also be made, and fusion proteins expressed, as discussedherein using methods known in the art.

Example 3 Transient Expression of Fusion Proteins in 293-6E Cells andCHO-S Host Cells

The FGFR1-IIIc-Fc/pTT5 expression vector was designed to providetransient expression in 293-6E host cells. The 293-6E cells werepreviously adapted to serum-free suspension culture in Free-Style medium(Invitrogen; Carlsbad, Calif.). The cells were transfected with theexpression vector while in logarithmic growth phase (log phase growth)at a cell density of between 9×10⁵/ml and 1.2×10⁶/ml.

In order to transfect 500 ml of cell suspension, a transfection mixturewas first made by mixing 500 micrograms (ug) of the expression vectorDNA in 25 milliliters (ml) of sterile phosphate buffered saline (PBS)with 1 milligram (mg) of polyethylenimine (at a concentration of about 1mg/ml solution in sterile water) in 25 ml of sterile PBS. Thistransfection mixture was incubated for 15 min at room temperature.Following incubation, the transfection mixture was added to the 293-6Ecells in log phase growth to transfect the cells. The cells and thetransfection mixture were then incubated at 37° C. in 5% CO₂. After 24hr of incubation, Trypton-N1 (Organotechnie S.A.; La Courneuve, France;20% solution in sterile FreeStyle medium) was added to a finalconcentration of 0.5% (v/v). The mixture was maintained at 37° C. and 5%CO₂ for about 6-8 days until the cells reached a density of about3-4×10⁶ cells/ml and demonstrated greater than about 80% viability. Toharvest the fusion protein from the cell culture medium, cells werepelleted at 400×g for 15 min at 4° C. and the supernatant decanted thencleared of cell debris by centrifugation at 3,315×g for 15 min at 4° C.The cleared supernatant containing the fusion protein was then purified,as described in more detail below.

The FGFR fusion proteins FGFR3-IIIc-Fc, FGFR4-Fc, and the FGFR fusionvariants R1Mut1, R1Mut2, R1Mut3, R1Mut4, R1Mut5, R1Mut6, R1Mut7, R1Mut8,and R1Mut9 were similarly produced by transient expression in 293-6Ecells in pTT5 vectors constructed as described in Example 2. OtherFGFR-Fc fusion proteins and variants can also be similarly made andexpressed in 293-6E host cells using the methods discussed herein.

Small batches (approximately 1-2 mg) of R1Mut4 protein, for example, foruse in in vivo studies, were rapidly produced from CHO-S cells grown insuspension and transiently transfected with the plasmid constructR1Mut4/pcDNA3.1. Briefly, suspension CHO-S cells (Invitrogen; Carlsbad,Calif.) were cultured in CD-CHO serum free medium supplemented withL-glutamine, and 1× hypoxanthine/thymidine (HT) (Invitrogen; Carlsbad,Calif.). The day before transfection, CHO-S cells were seeded into ashaker flask at a density of about 5×10⁵/ml and reached a density ofabout 1×10⁶/ml on the day of transfection. The cells were harvested andabout 1×10⁷ cells per transfection reaction were pelleted bycentrifugation. Each cell pellet was resuspended in 0.1 ml NucleofectorV solution and transferred to an Amaxa Nucleofector cuvette (Amaxa;Cologne, Germany). About 5 ug of the R1Mut4/pcDNA3.1 plasmid DNA wasadded and mixed with the suspended CHO-S cells in the cuvette. Cellswere then electroporated with an Amaxa Nucleofector using program U-024.

Larger batches can be produced, as well. For example, to produce 200 ml,12 transfection reactions were carried out and the electroporated cellswere cultured in CD-CHO medium (supplemented with L-glutamine, 1×hypoxanthine/thymidine (HT) at density of 0.5×10⁶/ml. After six days,the cell density reached about 6-7×10⁶/ml with a viability of about 95%.The supernatant from the culture was harvested by centrifugation and wassuitable for purification. Using this method, one mg of R1Mut4 proteincan be produced in about one week from 200 ml of transiently transfectedcultured cells.

The FGFR fusion proteins FGFR1-IIIc-Fc, FGFR3-IIIc-Fc, and FGFR4-Fc, andthe variants R4Mut1, R4Mut2, R4Mut3, R4Mut4, R4Mut5, and R4Mut6 weresimilarly produced by transient expression in CHO-S cells in pcDNA3.1vectors constructed as described in Example 2. Other FGFR-Fc fusionproteins and variants can also be made and expressed in CHO-S host cellsusing the methods discussed herein.

Example 4 Cell Line Development for Stable Production of Fusion Proteinsin CHO-S Host Cells

The FGFR1-IIIc-Fc/pcDNA3.1 expression vector was designed to providestable expression in appropriate mammalian cells, such as CHO-S. Thisvector was transfected into CHO-S cells containing the dihydrofolatereductase (DHFR) gene, which were derived from adherent CHO-K1 cells byadaptation to serum-free suspension culture in CD-CHO medium(Invitrogen; Carlsbad, Calif.).

Transfection was carried out using an Amaxa Nucleofector II (Amaxa;Cologne, Germany) according to manufacturer's recommendations. In thisprocess, about 1×10⁶ CHO-S cells were resuspended in 300 ul of Amaxa'sSolution V (Amaxa; Cologne, Germany) and transferred into anelectroporation cuvette. About 5 ug of plasmid DNA containing theFGFR1-IIIc-Fc/pcDNA3.1 expression vector was added to the cells in thecuvette and DNA transfer was initiated using Amaxa program U-024 inAmaxa's Nucleofector Device II. After the DNA transfer to the CHO-Scells, the cell suspension was immediately transferred into 1 ml ofpre-warmed CD-CHO medium and then incubated at 37° C. for 10 min. Thecell suspension was then transferred into 10 ml of pre-warmed CD-CHOmedium and cultured for 48 hr in a T-75 flask at 37° C. and 5% CO₂. Thevector pcDNA3.1 carried the G418-selection gene (Invitrogen; Carlsbad,Calif.). About 48 hr after the DNA transfer with FGFR1-IIIc-Fc/pcDNA3.1,G418 (Invitrogen; Carlsbad, Calif.) selection reagent was added to afinal concentration of 400 ug/ml. About 2-3 weeks after introducingselective pressure, and when the cells reached confluency, they wereexpanded into T-225 flasks with fresh selection medium. The cells werethen cryo-preserved until use.

The cryo-preservation medium contained 46.25% CD-CHO medium, 46.25%conditioned CD-CHO medium (usually supernatant from the culture beingcryo-preserved) and 7.5% dimethyl sulfoxide (DMSO). About 5-10×10⁶cells/vial were resuspended in 1 ml of cryo-preservation medium andslowly frozen (about 1° C./min) to about −80° C. The following day, thefrozen cells were transferred into liquid N₂ (about −190° C.). Upon use,the cells were thawed quickly, by transferring the cryo-vial into a 37°C. water bath and resuspending the thawed cell suspension in at least 10ml of fresh CD-CHO medium. Usually about 60% of the cells would recoverand start proliferating about 24-48 hr after thawing.

Following cryo-preservation and recovery, the cells were plated on96-well plates at a density of 2 cells/well/200 ul and cultured inCD-CHO medium at 37° C. and 5% CO₂ for three weeks. G418 selectivepressure (400 ug/ml) was added after cell proliferation resumed. Inorder to identify transfected cell clones expressing FGFR1-IIIc-Fcfusion protein, the cell culture supernatant of each well was screenedby Western blot. FGFR1-IIIc-Fc was detected using a polyclonal goatanti-human IgG Fc gamma-specific antibody (Jackson Immuno Research; WestGrove, Pa.) conjugated to horseradish peroxidase (HRP).

FGFR1-IIIc-Fc produced from transfected CHO-S cells had a highermolecular weight than that produced from transfected 293-6E cells,indicating increased glycosylation in the CHO-S cell product. Thirty-onecell clones from wells which produced a distinct Fc-immunoreactive bandin Western blot were transferred to T-75 flasks with 10 ml of CD-CHOmedium with 400 ug/ml G418. After two weeks, supernatants from each ofthese cultures was tested by SDS-PAGE and only those transfected cellclones producing a strongly visible band were continued for furtheranalysis. The 14 highest expressing clones were tested for cell specificproductivity and ranked accordingly. The two highest producing cloneswere adapted to suspension culture over a period of one month. A totalof ten different culture media were tested regarding volumetric proteinproductivity and protein integrity.

Stable CHO-S host cell lines producing FGFR4-Fc fusion protein from thepcDNA3.1 expression vector were also created in a manner similar to thatdescribed above for FGFR1-IIIc-Fc. Stable CHO-S host cell linesproducing other FGFR-Fc fusion proteins and variants can also be createdin a manner similar to that described herein, using the pcDNA3.1expression vector described in Example 2.

Example 5 Cell Line Development for Stable Production of Fusion Proteinsin DG44 Cells

The expression vector comprising R1Mut4/pDEF38 described in Example 2was used to transfect DG44 cells for the stable production of R1Mut4fusion protein. In this process, the untransfected DHFR-negative CHOcell line, DG44, was cultured in CHO-CD serum free medium (IrvineScientific; Irvine, Calif.) supplemented with 8 mM L-glutamine, 1×hypoxanthine/thymidine (HT; Invitrogen; Carlsbad, Calif.), and 18 ml/Lof Pluronic-68 (Invitrogen; Carlsbad, Calif.). About 50 ug of plasmidDNA containing R1Mut4/pDEF38 was first linearized by digestion with therestriction enzyme PvuI, then precipitated by addition of ethanol,briefly air-dried, and subsequently resuspended in 400 ul of sterile,distilled water. Cultured DG44 cells, as host cells, were seeded into ashaker flask at a cell density of about 4×10⁵/ml the day beforetransfection, and reached a density of about 0.8×10⁶/ml on the day oftransfection. The cells were harvested and about 1×10⁷ cells pertransfection unit were pelleted by centrifugation

The cells were transfected by resuspending each cell pellet in 0.1 ml ofNucleofector V solution and transferred the suspension to an AmaxaNucleofector cuvette (Amaxa; Cologne, Germany). About 5 ug of theresuspended linearized plasmid DNA was added and mixed with thesuspended DG44 cells in the cuvette. Cells were then electroporated withan Amaxa Nucleofector Device II using program U-024. Electroporatedcells were cultured in CHO-CD medium for two days and then transferredinto a selective medium comprising CHO-CD serum free medium supplementedwith 8 mM L-glutamine, 18 ml/L Pluronic-68, and 10% dialyzed fetal calfserum (FCS; Invitrogen; Carlsbad, Calif.; without HT). This selectivemedium was changed once every week. After about 12 days, 1 ug/ml R3 LongIGF I growth factor (Sigma; St. Louis, Mo.) was added to the medium andthe culture was continued for another four days until confluent. Thesupernatants from pools of stably transfected cell lines were assayed bya sandwich FGFR1-IIIc-Fc ELISA to determine the product titer (fordetails of this sandwich ELISA, see Example 15). This transfectionmethod generated an expression level of about 21 ug/ml for R1Mut4 fromthe pools of stably transfected cells.

Stable DG44 host cell lines producing FGFR1-IIIc-Fc fusion protein fromthe pDEF38 expression vector were also created in a manner similar tothat described herein for R1Mut4. Stable DG44 host cell lines producingother FGFR-Fc fusion proteins and variants can also be created in asimilar manner described herein, using the pDEF38 expression vectordescribed in Example 2.

Example 6 Analysis of In Vitro Cleavage of FGFR1-IIIc-Fc, R1Mut4 andOther FGFR1-IIIc-Fc Variants During Cell Culture Production

The resistance of FGFR1-IIIc-Fc to in vitro cleavage during transientprotein expression was compared to the FGFR1-IIIc-Fc variants R1Mut1,R1Mut2, R1Mut3, R1Mut4, R1Mut5, R1Mut6, R1Mut7, R1Mut8 and R1Mut9.Fusion proteins were each expressed in 293-6E cells via transienttransfection using the pTT5 vector as described in Example 2. Thesupernatants of each transfectant were collected on day fourpost-transfection and about 5 ul of each was separated with SDS-PAGE ina 4-12% acrylamide gel under reducing conditions. The supernatants werefrom cultures that were matched for cell number, viability, andtransfection conditions. The separated proteins were then probed withhorseradish-peroxidase conjugated anti-human Fc antibody (anti-human FcHRP; Jackson ImmunoResearch Laboratories, Inc.; West Grove, Pa.). Theresults are shown in FIG. 3A, which shows the Fc fragment cleaved fromthe parental FGFR1-IIIc-Fc migrating between approximately 28 and 39 kD.Much less Fc product was cleared when the fusion protein was made withthe truncation variants R1Mut1, R1Mut2, R1Mut3, R1Mut4, and R1Mut5.Similar experiments demonstrated that the variants of FGFR1-IIIc-FcR1Mut6, R1Mut7, also had less in vitro cleavage during transient proteinexpression than the parental FGFR1-IIIc-Fc fusion protein.

To compare the in vitro cleavage of FGFR1-IIIc-Fc and R1Mut4 producedfrom stably transfected DG44 host cells, pooled supernatants fromcultures of cells producing FGFR1-IIIc-Fc and R1Mut4 having similar cellviability (82.9% for FGFR1-IIIc-Fc and 79.2% for R1Mut4), the samecultivation period (four days), and having similar cell densities(0.95×10⁶/ml for FGFR1-IIIc-Fc and 0.65×10⁶/ml for R1Mut4). Theexpressed recombinant proteins were separated on a 4-12% Bis-Tris PAGEgel (Bio-Rad; Hercules, Calif.) and subsequently transferred to anitrocellulose membrane. The intact molecule, as well as the cleavedproduct of free human Fc fragment, was visualized by Western blot usinggoat anti-human Fc antibody (Jackson ImmunoResearch Laboratories, Inc.;West Grove, Pa.). The results are shown in FIG. 3B. The left panel ofthe Western blot shows 50 ng, 100 ng, and 300 ng of purifiedFGFR1-IIIc-Fc protein produced from CHO-S cells. The right panel shows acomparison of FGFR1-IIIc-Fc and R1Mut4 supernatants produced from DG44cells, revealing the presence of an Fc cleavage product from theFGFR1-IIIc-Fc but little or no Fc cleavage product from the R1Mut4.These results indicate that R1Mut4 was more resistant to proteolysis andhad less product cleaved during production than its parent moleculeFGFR1-IIIc-Fc.

The resistance of parental FGFR4-Fc to in vitro cleavage duringtransient protein expression was compared to the FGFR4-Fc variantsR4Mut1, R4Mut2, R4Mut3, R4Mut4, R4Mut5, and R4Mut6 (delta GS). Fusionproteins were each expressed in 293-6E cells via transient transfectionusing the pTT5 vector and the techniques described in Example 2. Thesupernatants of each transfectant were collected on days seven and eightpost-transfection and about 5 ul of each was separated by SDS-PAGE in a4-12% acrylamide gel under reducing conditions. The supernatants wereobtained from cultures matched for cell number, viability, andtransfection conditions. The separated proteins were then probed withhorseradish-peroxidase conjugated anti-human Fc antibody (anti-human FcHRP; Jackson ImmunoResearch Laboratories, Inc., West Grove, Pa.). Theresults are shown in FIG. 4. The Fc fragment was cleaved from theparental FGFR4-Fc and migrated between approximately 30 and 43 kD. Muchless Fc product cleaved when the fusion protein was made with thetruncation variants R4Mut1, R4Mut3, and R4Mut4 compared to the parentalconstruct, R4Mut2, R4Mut5, and R4Mut6.

Example 7 Purification of FGFR1-IIIc-Fc

FGFR1-IIIc-Fc expressed from recombinant host cells was purified fromcell culture supernatant using a combination of Protein-A affinitychromatography and butyl hydrophobic interaction chromatography. Thecomponents of the media were separated first on a Protein-A Sepharosecolumn, then on a butyl Sepharose column using a GE Healthcare AktaPurifier 100 (GE Healthcare Bio-Sciences; Piscataway, N.J.). TheProtein-A Sepharose 4 Fast Flow (GE Healthcare Bio-Sciences; Piscataway,N.J.) was used as an affinity matrix to bind to the Fc region of thefusion molecule. The column was equilibrated with ten column volumes ofa sterile buffer of 10 mM potassium phosphate, 500 mM NaCl, pH 7.0; thenthe cell culture supernatant fluid was applied to the column. The columnwas washed with eight column volumes of sterile 10 mM potassiumphosphate, 500 mM NaCl buffer, pH 7.0; then the bound material,including FGFR1-IIIc-Fc, was eluted at a rate of 10 ml/min with a stepgradient of the elution buffer (100 mM glycine, 500 mM NaCl, pH 2.7)using sequential steps of two column volumes each of 15%, 30%, 45%, 60%,75%, and 90% elution buffer, followed by five column volumes of 100%elution buffer. Ten-ml fractions were collected in tubes containing oneml 1 M Tris pH 7.0 (Ambion; Austin, Tex.) to neutralize the eluates.Fractions comprising FGFR1-IIIc-Fc were identified by gelelectrophoresis and pooled. FGFR1-IIIc-Fc was eluted at approximately30-45% gradient-strength elution buffer.

Pooled Protein-A column eluates comprising the bulk of FGFR1-IIIc-Fcwere then subjected to further purification by butyl Sepharosehydrophobic interaction chromatography. Following the addition of anequal volume of 2.4 M ammonium sulfate to the eluate from the Protein-Acolumn, the eluate was applied to a Butyl Sepharose 4 Fast Flow column(GE Healthcare Bio-Sciences; Piscataway, N.J.) that had beenequilibrated with five column volumes of sterile 10 mM potassiumphosphate, 1.2 M ammonium sulfate, pH 7.0. The column was washed withfour column volumes of the equilibration buffer and the bound materialwas eluted at a rate of five ml/min with a linear gradient starting at100% equilibration buffer and ending at 100% of the elution buffer (10mM potassium phosphate, 30 mM NaCl, pH 7.0) over a total volume of 13column volumes followed by an additional five column volumes 100%elution buffer. Fractions (14 ml) were collected and the fractionscontaining the bulk of FGFR1-IIIc-Fc were identified by gelelectrophoresis and pooled. FGFR1-IIIc-Fc was eluted with approximately20-50% elution buffer.

After purification, endotoxin levels were checked by the limulusamoebocyte lysate (LAL) assay (Cambrex; Walkersville, Md.). When thevalues were higher than 1 endotoxin unit (EU)/mg of FGFR1-III-Fcprotein, further purification was performed by Cellufine™ ETCleanchromatography (Chisso Corporation; Tokyo, Japan) following themanufacturer's instructions. FGFR1-IIIc-Fc was dialyzed with PBS andapplied to a Cellufine™ ET Clean column (10×0.9 cm (I.D.); 9.6 ml)previously equilibrated with PBS, and the protein was collected in theflow through at a flow rate of 0.5 ml/min. The final FGFR1-IIIc-Fcsolution (in PBS without Ca²⁺/Mg²⁺) was then re-tested to confirm avalue less than or equal to 1 EU/mg of protein as assessed by the LALassay.

These purification protocols were used to purify other FGFR-Fc fusionproteins and variants, such as FGFR3-IIIc-Fc and R1Mut4. Thesepurification protocols may also be used to purify other FGFR-Fc fusionproteins and variants, and may be adjusted using methods known in theart to substantially purify FGFR-Fc fusion proteins, for example, otherFGFR1-Fc fusion protein variants, FGFR2-Fc fusion proteins and variants,FGFR3-IIIc-Fc fusion protein variants, and FGFR4-Fc proteins andvariants. For example, components of the cell culture supernatant mediamay be separated by hydrophobic chromatography either prior to orsubsequent to the Protein-A step. Both the Protein-A and hydrophobicchromatography can take place in a column, a slurry, or other similarembodiments. The column size may depend on the amount of FGFR-Fcestimated to be present in the cell culture supernatant, for example, 25liters of CHO cell supernatant media transfected with FGFR1-IIIc-Fcproduced about 8 mg/L, or 200 mg of substantially pure FGFR1-IIIc-Fc,using the protocol described above.

Example 8 Specificity and Affinity of Ligand Binding to FGFR1-IIIc-Fc,R1Mut4, FGFR3-IIIc-Fc, and FGFR4 Measured by Biacore Analysis

The specificity of FGF ligand binding to FGFR1-IIIc-Fc, R1Mut4,FGFR3-IIIc-Fc, and FGFR4-Fc was assessed using Biacore® T100 surfaceplasmon resonance (SPR) technology (Biacore; Piscataway, N.J.).FGFR1-IIIc-Fc, R1Mut4, and FGFR4-Fc fusion proteins were produced fromCHO-S host cells as described in Examples 2, 4, and 5. FGFR3-IIIc-Fcfusion protein was produced from 293-6E host cells as described inExamples 2 and 3. Protein-A was covalently linked to a CM5 chip,according to manufacturer's instructions and then a FGFR fusion proteinwas bound to the chip by the interaction of the Fc domain with theProtein-A. The FGF ligands were placed in contact with the FGFR fusionprotein, also according to manufacturer's instructions, in the presenceof HBS-P buffer (Biacore; Piscataway, N.J.) supplemented with 50 ug/mlheparin (Sigma; St. Louis, Mo.).

All the recombinant FGF ligands were from R&D Systems (Minneapolis,Minn.) except for FGF-18 which was from Wako Chemicals (Richmond, Va.).FGF ligands were each tested at six to eight concentrations ranging from4.5 ng/ml to 10 ug/ml. The FGF ligands were recombinant and of humanorigin, except for FGF8b and FGF-18, which were of recombinant mouseorigin.

The binding of FGFR1-IIIc-Fc, R1Mut4, FGFR3-IIIc-Fc, and FGFR4-Fc tovarious FGF ligands was measured in real time. FIG. 32 shows severalrepresentative binding traces from the experiments with FGFR1-IIIc-Fcand R1Mut4 and Table 3 below shows the resulting association constants(k_(a)), dissociation constants (k_(d)) and equilibrium dissociationconstants (K_(D)) that were determined from these studies.

As summarized in Table 8-1, the relative rank of FGF binding affinity toFGFR1-IIIc-Fc was FGF-1>FGF-18>FGF-2, FGF-4>FGF-9, FGF-20>FGF-5>FGF-19.The relative rank of FGF binding affinity to R1Mut4 was FGF-1>FGF-4,FGF-18>FGF-2>FGF20>FGF-9>FGF-5>FGF-19. The relative rank of FGF bindingaffinity to FGFR3-IIIc-Fc was FGF-18>FGF-1>FGF-9>FGF-2,FGF-4>FGF-20>FGF-5>FGF-7>FGF-19. The relative rank of FGF bindingaffinity to FGFR4-Fc was FGF-1>FGF-2.

In another binding study between FGFR4-Fc and the various FGFs,conducted in a similar fashion as described above, the resultingequilibrium dissociation constants (K_(D)) and the relative rank of FGFbinding affinity for FGFR4-Fc were: FGF-18 (K_(D) of 0.4×10⁻⁹M)>FGF-17(K_(D) of 1.0×10⁻⁹M)=FGF-20 (K_(D) of 1.2×10⁻⁹M)>FGF-8 (K_(D) of3.9×10⁻⁹M)=FGF-4 (K_(D) of 4.6×10⁻⁹M)>FGF-9 (K_(D) of 9.8×10⁻⁹M)=FGF-16(K_(D) of 9.7×10⁻⁹M)>FGF-19 (K_(D) of 12.3×10⁻⁹M)>FGF-1 (K_(D) of16.3×10⁻⁹M)>FGF-6 (K_(D) of 26.2×10⁻⁹M)>FGF-2 (K_(D) of44.2×10⁻⁹M)>FGF-3 (K_(D) of 51.8×10⁻⁹ M). FGF-5 showed no binding inthis experiment.

The affinity of R1Mut4 for all the ligands tested except FGF-19 wasgreater than that of the parental FGFR1-IIIc-Fc molecule. In addition,the relative rankings of ligand affinities were also different betweenR1Mut4 and the parental FGFR1-IIIc-Fc molecule.

TABLE 3 Real-Time Ligand Binding to FGFRs FGFR1-IIIc-Fc R1Mut4 Ligandk_(a) k_(d) K_(D) k_(a) k_(d) K_(D) FGF-1 2.00 × 10⁶ M 1.99 × 10⁻⁴ M9.95 × 10⁻¹¹ M 3.46 × 10⁶ M* 1.61 × 10⁻⁴ M* 5.07 × 10⁻¹¹ M* FGF-2 3.75 ×10⁵ M 2.31 × 10⁻⁴ M 6.17 × 10⁻¹⁰ M 4.12 × 10⁵ M 1.80 × 10⁻⁴ M 4.38 ×10⁻¹⁰ M FGF-4 7.15 × 10⁵ M 4.77 × 10⁻⁴ M 6.67 × 10⁻¹⁰ M 1.06 × 10⁶ M2.26 × 10⁻⁴ M 2.14 × 10⁻¹⁰ M FGF-5 1.71 × 10⁵ M 7.85 × 10⁻⁴ M 4.58 ×10⁻⁹ M 3.71 × 10⁵ M 9.65 × 10⁻⁴ M 2.95 × 10⁻⁹ M FGF-7 n.d n.d n.d n.dn.d n.d FGF-9 4.74 × 10⁵ M 5.29 × 10⁻⁴ M 1.12 × 10⁻⁹ M 5.66 × 10⁵ M 5.10× 10⁻⁴ M 9.19 × 10⁻¹⁰ M FGF-18 1.11 × 10⁶ M* 4.41 × 10⁻⁴ M* 4.18 × 10⁻¹⁰M* 1.06 × 10⁶ M* 2.77 × 10⁻⁴ M* 2.75 × 10⁻¹⁰ M* FGF-19 5.63 × 10⁴ M 4.43× 10⁻¹ M 7.87 × 10⁻⁶ M n.m. n.m. n.m. FGF-20 1.62 × 10⁵ M 2.55 × 10⁻⁴ M1.57 × 10⁻⁹ M 2.42 × 10⁵ M 1.90 × 10⁻⁴ M 7.85 × 10⁻¹⁰ M FGFR3-IIIc-FcFGFR4-Fc Ligand k_(a) k_(d) K_(D) k_(a) k_(d) K_(D) FGF-1 2.83 × 10⁶ M*3.31 × 10⁻⁴ M* 1.26 × 10⁻¹⁰ M* 1.68 × 10⁵ M 5.78 × 10⁻⁴ M 3.45 × 10⁻⁹ MFGF-2 3.36 × 10⁵ M 1.37 × 10⁻³ M 1.06 × 10⁻⁹ M 4.16 × 10⁴ M 6.73 × 10⁻⁴M 1.62 × 10⁻⁸ M FGF-4 8.08 × 10⁵ M 1.55 × 10⁻³ M 1.91 × 10⁻⁹ M n.m. n.m.n.m. FGF-5 2.31 × 10⁵ M 1.69 × 10⁻³ M 9.70 × 10⁻⁹ M n.d n.d n.d FGF-73.19 × 10⁵ M 4.71 × 10⁻² M 1.48 × 10⁻⁷ M n.d n.d n.d FGF-9 7.76 × 10⁵ M4.17 × 10⁻⁴ M 5.37 × 10⁻¹⁰ M n.d n.d n.d FGF-18 5.16 × 10⁶ M* 1.80 ×10⁻⁴ M* 3.50 × 10⁻¹¹ M* n.d n.d n.d FGF-19 5.63 × 10⁴ M 4.43 × 10⁻¹ M7.87 × 10⁻⁶ M n.d n.d n.d FGF-20 1.85 × 10⁵ M 4.04 × 10⁻⁴ M 2.17 × 10⁻⁹M n.d n.d n.d *= average of two independent measurements n.d. = notdetermined n.m. = not measurable

Example 9 Specificity and Affinity of Ligand Binding to FGFR4-Fc andFGFR4-Fc Deletion Mutants Measured by Competition ELISA

FGFR4-Fc fusion protein and deletion variants, made as described inExamples 1, 2, and 3, were tested for their ability to sequester thesoluble FGF ligands FGF-1, FGF-2, and FGF-8b, and to inhibit ligandbinding to FGFR4-Fc fusion protein coated on a plate.

Briefly, HI BIND half-wells were coated with FGFR4-Fc of CHO-S-origin ata concentration of 5 ug/ml in PBS in a volume of 25 ul per well for 1 hrat room temperature. The wells were blocked by adding 150 ul BLOTTO perwell and incubating for 2 hr at room temperature. The coated half-wellplates were then washed six times with PBS and 0.05% Tween-20 to removeunbound FGFR1-IIIc-Fc and BLOTTO.

Varying amounts of FGFR4-Fc fusion protein and the deletion variants,produced from CHO-S cells, or 10 ug/ml of the negative control human IgG(Caltag; Burlingame, Calif.) were each first pre-incubated in 96-wellU-bottom plates with 60 ng/ml recombinant human FGF-1 (from R&D Systems;Minneapolis, Minn.) in 50 ul for 30 min at 37° C. on a shaker in thepresence of 20 ug/ml heparin in 0.1×BLOTTO in PBS. About 40 ul of theabove fusion proteins pre-incubated with FGF-1 were then added to thewashed half-well plates coated with FGFR4-Fc and incubated for 30 min at37° C. with shaking. After incubation, the plates were washed as beforesix times with PBS and 0.05% Tween-20 to remove any unbound FGF-1. Afterwashing, about 2 ug/ml of anti-human FGF-1 polyclonal biotinylatedantibody (R&D Systems; Minneapolis, Minn.) in 1× BLOTTO was added toeach well of the plate, which was then incubated for 30 min at 37° C.with shaking, followed by washing as before to remove any unboundanti-FGF-1 antibody. The bound anti-FGF-1 antibody was detected using astreptavidin-HRP linker provided in the ABC kit (Vector Laboratories;Burlingame, Calif.) according to manufacturer's protocol. After washingas before, reconstituted (OPD) solution (Sigma; St. Louis, Mo.) wasadded. The detection reaction proceeded for 10 to 20 min at roomtemperature and was followed by a reading of the absorbance at 450 nm.The binding curves from the competition ELISA and the resulting EC₅₀values are shown in FIG. 5A.

FIG. 5A showed that the FGFR4 deletion variants R4Mut1, R4Mut2, R4Mut3,R4Mut4, R4Mut5, and R4Mut6 had higher affinities for FGF-1 than did theparental FGFR4-Fc. The FGFR4-Fc deletion variants had EC₅₀ values ofabout 0.033 ug/ml to about 0.057 ug/ml. In contrast, the parentalFGFR4-Fc had an EC₅₀ value of about 0.123 ug/ml. The human IgG1 negativecontrol did not inhibit FGF-1 binding to the FGFR4-Fc coated on theplate.

Similar competition ELISA experiments were conducted comparing theability of the FGFR4-Fc fusion protein and the FGFR4-Fc deletionvariants, produced in CHO-S host cells, to inhibit the binding ofrecombinant human FGF-2 (used at 200 ng/ml) and recombinant mouse FGF-8b(used at 200 ng/ml) (all from R&D Systems; Minneapolis, Minn.) toFGFR4-Fc derived from CHO-S cells and immobilized on an assay plate.

FIG. 5B showed that the FGFR4 deletion variants R4Mut1, R4Mut2, R4Mut3,R4Mut4, and R4Mut5 had higher affinities for FGF-2 than did the parentalFGFR4-Fc. The FGFR4-Fc deletion variants R4Mut1, R4Mut2, R4Mut3, R4Mut4,and R4Mut5 had EC₅₀ values from about 0.091 ug/ml to about 0.457 ug/ml,with R4Mut3 having the highest affinity for FGF-2; the EC₅₀ was about0.091 ug/ml. In contrast, the parental FGFR4-Fc had an EC₅₀ value ofgreater than 10 ug/ml, as did the deletion variant R4Mut6. The humanIgG1 negative control did not inhibit FGF-1 binding to plate-immobilizedFGFR4-Fc.

FIG. 5C showed that the FGFR4 deletion variants R4Mut1, R4Mut2, R4Mut3,R4Mut4, R4Mut5, and R4Mut6 had higher affinities for FGF-8b than did theparental FGFR4-Fc. The FGFR4-Fc deletion variants had EC₅₀ values ofabout 0.137 ug/ml to about 0.209 ug/ml. In contrast, the parentalFGFR4-Fc had an EC₅₀ value of about 0.631 ug/ml. The human IgG1 negativecontrol did not inhibit FGF-1 binding to the FGFR4-Fc coated on theplate.

These experiments demonstrated that the FGFR4 deletion mutants R4Mut1,R4Mut2, R4Mut3, R4Mut4 and R4Mut5 had a higher affinity than theparental FGFR4-Fc in their ability to inhibit FGF-1 (as shown in FIG.5A), FGF-2 (as shown in FIG. 5B), and FGF-8b (as shown in FIG. 5C)binding to plate-immobilized FGFR4-Fc.

Example 10 Affinity of Ligand Binding to FGFR1-IIIc-Fc Deletion MutantsMeasured by Direct ELISA

The R1Mut1, R1Mut2, R1Mut3, R1Mut4, and R1Mut5 fusion proteins werecompared to parental FGFR1-IIIc-Fc fusion protein (all produced from293-6E host cells as described in Example 3) for their ability to bindFGF-2 by a direct FGF-2 binding ELISA assay. Briefly, FGF-2 (R&DSystems; Minneapolis, Minn.) was used to coat half-well HI BIND wells(Becton Dickinson; Franklin Lakes, N.J.) by diluting FGF-2 in PBS at aconcentration of 5 ug/ml in 25 ul volume per well and incubating for 1hr at room temperature while shaking. The wells were then blocked byadding 150 ul of BLOTTO (Pierce Biotechnology; Rockford, Ill.) to eachwell and incubating for 1 hr at room temperature. The plates were thenwashed six times with PBS comprising 0.05% Tween-20 to remove the FGF-2and BLOTTO and the wells were then incubated overnight at 4° C. withvarying concentrations of FGFR1-IIIc-Fc, R1Mut1, R1Mut2, R1Mut3, R1Mut4,R1Mut5, or human IgG (as a negative control), in the presence of 10ug/ml heparin diluted in 0.1×BLOTTO in PBS. The plates were washed asbefore, and then incubated with 25 ul of anti-human Fc antibodyconjugated to HRP at 2.5 ug/ml in BLOTTO for 1 hr at room temperature ona plate shaker. The BLOTTO was then removed and the plates were againwashed as before. After washing, the wells were incubated withreconstituted OPD solution (Sigma; Saint Louis, Mo.) for 10 to 20 min atroom temperature and the absorbance at 450 nm was measured.

As shown in FIG. 6, R1Mut1, R1Mut2, R1Mut3, and R1Mut4, but not R1Mut5,were each able to bind to FGF-2 as well as or better than the parentalFGFR1-IIIc-Fc, with R1Mut4 having the highest apparent affinity of allthe fusion proteins tested in this experiment. The MMP-2 cleavage sitemutants R1Mut7, R1Mut8, and R1Mut9 (all produced in 293-6E host cellsusing the expression vector pTT5 as described in Example 2) also boundto FGF-2 with an affinity similar to that of parental FGFR1-IIIc-Fc.

Example 11 FGFR Fusion Proteins Inhibit FGFR1-IIIc-Fc Ligand Binding

FGFR1-IIIc-Fc fusion proteins produced from 293-6E and CHO cells, madeas described in Examples 1, 2, and 3, were tested in a competition ELISAassay for their ability to sequester the soluble FGF ligands FGF-1,FGF-2, and FGF-8b, and to inhibit ligand binding to FGFR1-IIIc-Fc fusionprotein coated on a plate.

Briefly, HI BIND half-wells were coated with FGFR1-IIIc-Fc of293-6E-origin at a concentration of 5 ug/ml in PBS in a volume of 25 ulper well for 1 hr at room temperature. The wells were blocked by adding150 ul BLOTTO per well and incubating for 2 hr at room temperature. Thecoated half-well plates were then washed six times with PBS and 0.05%Tween-20 to remove unbound FGFR1-IIIc-Fc and BLOTTO.

Varying amounts of FGFR1-IIIc-Fc fusion proteins produced from 293-6Ecells or CHO cells, or 10 ug/ml of the negative control human IgG(Caltag; Burlingame, Calif.) were each first pre-incubated in 96-wellU-bottom plates with 200 ng/ml recombinant human FGF-2 (from R&DSystems) in 50 ul for 30 min at 37° C. on a shaker in the presence of 20ug/ml heparin in 0.1×BLOTTO in PBS. About 40 ul of the above fusionproteins pre-incubated with FGF-2 were then added to the washedhalf-well plates coated with FGFR1-IIIc-Fc and incubated for 30 min at37° C. with shaking. After incubation, the plates were washed as beforesix times with PBS and 0.05% Tween-20 to remove any unbound FGF-2. Afterwashing, about 2 ug/ml of anti-human FGF-2 polyclonal biotinylatedantibody (from R&D Systems) in 1×BLOTTO was added to each well of theplate, which was then incubated for 30 min at 37° C. with shaking,followed by washing as before to remove any unbound anti-FGF-2 antibody.The bound anti-FGF-2 antibody was detected using a streptavidin-HRPlinker provided in the ABC kit (Vector Laboratories, Burlingame, Calif.)according to the manufacturer's protocol. After washing as before,reconstituted OPD solution (Sigma; St. Louis, Mo.) was added. Thedetection reaction was developed for 10 to 20 min at room temperaturefollowed by a reading of absorbance at 450 nm. Results are shown in FIG.7.

FIG. 7 showed that FGFR1-IIIc-Fc produced from 293-6E and from CHO cellshad approximately equivalent binding potencies in their ability tosequester FGF-2 in an FGF-2 competition assay. Each of the two fusionproteins exhibited an EC₅₀ value of about 0.24 ug/ml. In contrast, thehuman IgG1 negative control did not inhibit FGF-2 binding to theFGFR1-IIIc-Fc coated on the plate.

Similar competition ELISA experiments were conducted comparing theability of the FGFR1-IIIc-Fc fusion protein and R1Mut4 fusion protein,both produced in DG44 host cells, to inhibit the binding of recombinanthuman FGF-1 (at a concentration of 60 ng/ml), recombinant human FGF-2 (aconcentration of at 200 ng/ml), and recombinant mouse FGF-8b (aconcentration of at 200 ng/ml) (all from R&D Systems; Minneapolis,Minn.) to FGFR1-IIIc-Fc derived from 293 cells and immobilized on anassay plate. These experiments all demonstrated the equivalency ofR1Mut4 and the parental FGFR1-IIIc-Fc fusion proteins in their abilityto inhibit FGF-1 (as shown in FIG. 8A), FGF-2 (as shown in FIG. 8B), andFGF-8b (as shown in FIG. 9) binding to plate-immobilized FGFR1-IIIc-Fc.

FGFR1-IIIc-Fc produced in DG44 host cells and FGFR3-IIIc-Fc and FGFR4-Fcproduced in 293-6E host cells also inhibited ligand binding toFGFR1-IIIc-Fc produced in 293 cells and immobilized on an assay plate. Acompetition ELISA assay conducted as described above used recombinanthuman FGF-1, recombinant human FGF-2, and recombinant mouse FGF-8b (allfrom R&D Systems; Minneapolis, Minn.). Human IgG was used as a negativecontrol. The results are shown in FIG. 10, FIG. 11, and FIG. 12, whichdemonstrate both the effectiveness of the decoy fusion proteins inblocking ligand-receptor binding and the specificity of the fusionproteins for their respective ligands.

FIG. 10 showed that FGFR1-IIIc-Fc, FGFR3-IIIc-Fc, and FGFR4-Fc allinhibited FGF-1 binding to FGFR1-IIIc-Fc immobilized on an assay plate.FIG. 11 showed that FGFR3-IIIc-Fc and FGFR4-Fc were much less effectivethan FGFR1-IIIc-Fc in inhibiting FGF-2 binding to FGFR1-IIIc-Fcimmobilized on an assay plate. FIG. 12 showed that FGFR1-IIIc-Fc,FGFR3-IIIc-Fc, and FGFR4-Fc were all similarly effective in inhibitingFGF-8 binding to FGFR1-IIIc-Fc immobilized on a plate.

Example 12 FGFR1-IIIc-Fc Inhibited Phospho-Erk Signaling by FGF-2

FGFR1-IIIc-Fc fusion protein derived from 293-6E or CHO cells wereapproximately equally potent in inhibiting biological signaling byFGF-2. L6 cells transfected with FGFR1-IIIc (ETH; Zurich, Switzerland)growing in a T-175 flask were trypsinized, washed and seeded at aconcentration of 10,000 cells/well in a volume of 100 ul in Dulbecco'smodified Eagle's medium (DMEM) supplemented with 0.5% FCS and 0.1%bovine serum albumin (BSA) in 96-well flat-bottom plates for 16 hr.Activation medium containing FGFR1-IIIc-Fc fusion proteins or humanIgG1, at concentrations from 0.005 to 10 ug/ml, was prepared (in 0.1%BSA DMEM containing 100 ng/ml FGF-2, 10 ug/ml heparin) and incubated for30 min at 37° C. on a plate shaker. The L6 cells were then exposed to 25ul of activation medium/well for 5 min at 37° C. The cells were thenwashed once with 200 ul of ice-cold PBS and lysed with 100 ul ofice-cold 1× lysis buffer for 30 min on ice following the manufacture'srecommendations for the PathScan Phospho-p44/42 MAPK (T202/Y204)Sandwich ELISA Kit (Cell Signaling; Danvers, Mass.). At the end of thelysis period, the lysates were pipeted up and down approximately fivetimes while minimizing foaming. About 80 ul of Sample Diluent (fromPathscan Sandwich ELISA kit) was added to each well of the phospho-ERKELISA plate, then topped by 80 ul of cell lysate and mixed. The platewas sealed with plastic adhesive, incubated for 2 hr at 37° C., andwashed six times with PBS containing 0.05% Tween-20. Then 100 ul ofphospho-ERK Detection Antibody (from Pathscan Sandwich ELISA kit) wasadded to each well. The plate was sealed with adhesive cover, incubatedfor 1 hr at 37° C., washed as before and 100 ul of HRP-linked secondaryantibody (from Pathscan Sandwich ELISA kit) was added to each well. Theplate was again sealed, incubated for 30 min at 37° C., and then washedas before. About 100 ul of TMB substrate (3,3′,5,5′-tetramethylbenzidine, from Pathscan Sandwich ELISA kit) was thenadded to each well and the plate was incubated for 30 min at 25° C. Thecolor development was completed by adding 100 ul of STOP Solution (fromPathscan Sandwich ELISA kit) to each well and mixing. The absorbance at450 nm was recorded and plotted as shown in FIG. 13.

FIG. 13 shows that Erk phosphorylation, as determined by ELISA, wassimilarly inhibited by FGFR1-IIIc-Fc made from either 293-6E or CHOcells. At the lower doses, FGFR1-IIIc-Fc blunted Erk activation and athigher doses, prevented activation by FGF-2. In the presence of 100ng/ml FGF-2, the EC₅₀ values of the 293 cells-derived and the CHOcells-derived FGFR1-IIIc-Fc were 0.23 ug/ml and 0.29 ug/ml,respectively. Human IgG1 did not inhibit Erk phosphorylation activatedwith FGF-2.

FGFR1-IIIc-Fc and R1Mut4 fusion proteins produced by 293-6E cellsinhibited Erk phosphorylation with approximately the same potency, incontrast to R1Mut5, which did not inhibit Erk phosphorylation. In thepresence of 0.10 ug/ml FGF-2, the EC₅₀ of FGFR1-IIIc-Fc was 0.18 ug/mland the EC₅₀ of R1Mut4 was 0.29 ug/ml. At low doses, both FGFR1-IIIc-Fcand R1Mut4 blunted Erk activation; and at high doses, both preventedactivation. Results are shown in FIG. 14.

Example 13 FGFR1-IIIc-Fc Decreased Cancer Cell Viability andProliferation

FGFR-Fc fusion proteins of the invention decreased the viability and/orproliferation of cancer cells in culture, as measured with aCellTiter-Glo™ Luminescent Cell Viability Assay according to themanufacturer's instructions (Promega; Madison, Wis.). In this assay,luminescence quantitatively correlates with the number of viable cells.

The effects of FGFR1-IIIc-Fc on U251 malignant glioblastoma brain cancercells obtained from the American Type Culture Collection (ATCC)(Manassas, Va.) are shown in FIGS. 15-17. The effect of FGFR1-IIIc-Fc oncell viability and proliferation was dependent on the concentration ofFGFR1-IIIc-Fc and on the growth conditions of the cells. The negativecontrol human IgG (20 ug/ml) had no effect. The positive control, TRAIL,decreased viability and proliferation. FGF-2 (100 ug/ml) stimulatedproliferation and differentiation. At the lower cell concentrationstested, FGF-2 did not blunt the inhibition induced by 20 μg/mlFGFR1-IIIc-Fc.

U251 cells were grown in DMEM with 4 mM L-glutamine adjusted to contain1.5 grams per liter (g/L) sodium bicarbonate and 4.5 g/L glucose, 10%heat-inactivated FCS with 100 units/ml penicillin and 100 ug/mlstreptomycin (pen-strep, Invitrogen; Carlsbad, Calif.) in T-150 flasksuntil they reached 70% to 90% confluency. The cells were treated with 10ml per flask of 0.25% trypsin solution in Hanks' Balanced Salt solution(Invitrogen; Carlsbad, Calif.) at room temperature for 3 min at 37° C.and the trypsin-cell suspension mixed with 40 ml of ice-cold 0.1% FCS inDMEM. The cells were pelleted at 900×g for 5 min at room temperature.This wash step was repeated with 50 ml of ice-cold 0.1% FCS in DMEM andthe cells resuspended in 5 ml of ice-cold 0.1% FCS in DMEM.

The resuspended U251 cells were plated in a volume of 150 ul per well in96-well flat-bottom tissue-culture grade plastic plates (Nunc;Rochester, N.Y.) in the presence of 20 ug/ml of porcine intestinalmucosa heparin (Sigma; St. Louis, Mo.). The cells were plated at threeculture conditions (1) a concentration of 1000 cells per well in thepresence of 10% FCS in DMEM with pen-strep; (2) a concentration of 5000cells per well in the presence of 1.0% FCS in DMEM with pen-strep; (3) aconcentration of 10,000 cells per well in the presence of 0.1% FCS inDMEM with pen-strep. The cells were treated with FGFR1-IIIc-Fc proteinor a control protein in four replicate wells per protein and incubatedfor five days in a humidified incubator at 37° C. with 5% CO₂. TheFGFR1-IIIc-Fc protein was made from 293-6E cells and substantiallypurified as described in Examples 2 and 7. The cells were treated withFGFR1-IIIc-Fc at a concentration of 20 ug/ml, 4 ug/ml, or 0.8 ug/ml.Control proteins included 20 ug/ml purified human IgG dialyzed againstPBS to remove preservative and then filter-sterilized (Caltag;Burlingame, Calif.) as a negative control, 100 ng/ml FGF-2 (R&D Systems;Minneapolis, Minn.), used either alone or in combination with 20 ug/mlFGFR1-IIIc-Fc as a positive control; and 10 ng/ml TRAIL (APO2ligand/tumor necrosis factor-related apoptosis-inducing ligand) (R&DSystems; Minneapolis, Minn.), used as a positive control.

Cell viability was then determined using the CellTiter-Glo™ LuminescentCell Viability Assay Kit (Promega; Madison, Wis.), according to themanufacturer's instructions. Briefly, 100 ul/well of reconstitutedCellTiter-Glo™ reagent was added to the cells and incubated for 10 minin the dark. The well contents were mixed by pipeting and 100 ul fromeach well were transferred to opaque, white 96-well plates (Corning;Acton, Mass.). The luminescent output from each well was read using a0.6 second per well recording time and the average relative luminescenceunits (RLU) of the four replicates were plotted along with theirstandard deviations.

As shown in FIG. 15, FGFR1-IIIc-Fc at each of the three concentrationstested reduced the viability and proliferation of cultured U251malignant glioblastoma cells plated at a concentration of 1000 cells perwell in 10% FCS. Untreated cells showed an RLU of about 480. Cellstreated with 20 ug/ml, 4 ug/ml, and 0.8 ug/ml FGFR1-IIIc-Fc showed anRLU of about 380, 400, and 400, respectively. Human IgG did not inhibitviability and proliferation, showing an RLU of about 500. FGF-2 aloneenhanced viability and proliferation, showing an RLU of about 600. Thecombination of FGF-2 and 20 ug/ml FGFR1-IIIc-Fc reduced cell viabilityand proliferation, showing an RLU of about 400. Treatment with TRAILresulted in almost complete inhibition, with an RLU of about 10.

As shown in FIG. 16, FGFR1-IIIc-Fc at each of the three concentrationstested reduced the viability and proliferation of cultured U251malignant glioblastoma cells plated at a concentration of 5000 cells perwell in 1.0% FCS. Untreated cells showed a RLU of about 360. Cellstreated with 20 ug/ml, 4 ug/ml, and 0.8 ug/ml FGFR1-IIIc-Fc showed anRLU of about 60, 140, and 200, respectively. Human IgG did not inhibitviability and proliferation, showing an RLU of about 400. FGF-2 aloneshowed an RLU of about 320. The combination of FGF-2 and 20 ug/mlFGFR1-IIIc-Fc reduced cell viability and proliferation, showing an RLUof about 90. Treatment with TRAIL resulted in almost completeinhibition.

As shown in FIG. 17, FGFR1-IIIc-Fc reduced the viability andproliferation of cultured U251 malignant glioblastoma cells plated at aconcentration of 10,000 cells per well in 0.1% FCS. These growthconditions generated more variability between wells, but FIG. 17demonstrates that FGFR1-IIIc-Fc inhibited the viability andproliferation of U251 cells in a fashion similar to that described inFIG. 15 and FIG. 16.

The effect of FGFR1-IIIc-Fc on the viability and proliferation of cancercells from cancer cell lines representing various solid tumor typesobtained from ATCC (Manassas, Va.) or NCI (Bethesda, Md.) was testedusing the CellTiter-Glo™ Luminescent Cell Viability Assay. The cellswere grown to about 70% to 90% confluency in T-150 flasks using therecommended growth media for each cell line. The cells were harvestedand treated in a manner similar to that described above for U251 cells.The cells were plated at a density of 1000 cells per well in thepresence of 10% FCS in DMEM, 5000 cells per well in the presence of 1.0%FCS in DMEM, or 10,000 cells per well in the presence of 0.1% FCS inDMEM; with 20 ug/ml FGFR1-IIIc-Fc as the test agent or 20 ug/ml humanIgG as the negative control.

The cancer cell lines tested included MDA-MB-435 (breast), MCF7(breast), MDA-MB-231 (breast), T47D (breast), A549 (lung), NCI-H522(lung), NCI-H460 (lung), NCI-H23 (lung), NCI-H226 (lung), U118 (brain),U87114 (brain), U251 (brain), SF268 (brain), WT11 (brain), DU145(prostate), PC-3 (prostate), COLO 205 (colon), Caki-1 (kidney), SK-MEL-2(skin) and SK-OV-3 (ovary). The results are shown in FIG. 18. Of the 20cancer cell lines tested, eight were susceptible to inhibition byFGFR1-IIIc-Fc under one or more of the growth conditions tested. Theeight susceptible cell lines were A549 (lung), NCI-H522 (lung), NCI-H226(lung), U118 (brain), U251 (brain), SF268 (brain), WT11 (brain), andCaki-1 (kidney).

Both FGFR1-IIIc-Fc and FGFR4-Fc inhibited the viability andproliferation of A549 lung carcinoma cells, as measured by theCellTiter-Glo™ Luminescent Cell Viability Assay. The FGFR1-IIIc-Fc andFGFR4-Fc proteins tested were produced in 293-6E cells via transienttransfection and purified as described in Examples 2 and 7. The effectof FGFR1-IIIc-Fc and FGFR4-Fc on A549 cells was tested using a protocolsimilar to that described above for U251 cells. The A549 cells wereseeded in four replicate wells at a density of 25,000 cells per well ina volume of 150 ul in flat-bottom 96-well plates in the presence of 20ug/ml porcine intestinal mucosa heparin (Sigma; Saint Louis, Mo.) in0.1% FCS DMEM with pen-strep. The A549 cells were cultured in thepresence of concentrations of FGFR1-IIIc-Fc protein or FGFR4-Fc proteinranging from about 0.0000095 ug/ml to about 10 ug/ml in four-fold serialdilutions for five days at 37° C. in 5% CO₂. Human IgG (10 ug/ml) wasused as a negative control. As shown in FIG. 19, cell viability andproliferation were expressed as percent inhibition (average RLU foruntreated-average RLU for sample)/(average RLU for untreated) times 100.The error bars show the % Error (standard deviation of sample/averagesample RLU) times 100.

At the higher concentrations tested, FGFR1-IIIc-Fc inhibited theviability and proliferation of A549 cells up to about 40%, as comparedto the IgG control. The IC₅₀ of FGFR1-IIIc-Fc was about 9.4 ng/ml,equivalent to 0.11 nanomolar (nM). At the highest concentration tested,FGFR4-Fc also inhibited the viability and proliferation of A549 cells upto about 40%, as compared to the IgG control. The IC₅₀ of FGFR4-Fc wasabout 100 ng/ml, equivalent to 1.2 nM; this is higher than that observedfor FGFR1-IIIc-Fc, reflecting a greater potency of FGFR1-IIIc-Fc thanFGFR4-Fc in inhibiting A549 cell viability and proliferation.

Example 14 FGFR-Fc Fusion Proteins Decreased Cancer Cell Viability andProliferation

FGFR1-IIIb-Fc, FGFR1-IIIc-Fc, FGFR2-IIIb-Fc, FGFR2-IIIc-Fc,FGFR3-IIIb-Fc, FGFR3-IIIc-Fc, and FGFR4-Fc were tested for the abilityto inhibit the viability and/or proliferation of six different cancercell lines. The seven fusion proteins tested in this assay were obtainedfrom a commercial source (R&D Systems). The cancer cell lines includedA549 (lung), U118 (brain), U251 (brain), SF268 (brain), T47D (breast)and Caki-1 (kidney).

The results obtained from the assays described in Example 13 providedthe basis for determining the number of cancer cells plated per well andthe concentration of FCS in their media. For instance, the A549 lungcarcinoma cells were plated at 25,000 cells per well in 150 ul of DMEMwith 0.1% FCS and pen-strep in a 96-well format. They were treated withtwo-fold serial dilutions of FGFR1-IIIc-Fc, FGFR2-IIIc-Fc,FGFR3-IIIc-Fc, or FGFR4-Fc ranging from about 0.078125 ug/ml to about5.0 ug/ml. Human IgG was used as a positive control, as described inExample 11. Each fusion protein treatment was performed in triplicatewells and each data point represents an average of three wells. Afterfive days of treatment, the cell viability of A549 cells was assayedwith the CellTiter-Glo™ Luminescent Cell Viability Assay as describedabove. The results are shown in FIG. 20 and indicated that the FGFR-Fcfusion protein inhibition of A549 cells was dose-dependent, reaching upto about 42% at the highest concentrations tested (5 ug/ml). Thepotencies of the fusion proteins were ranked asFGFR1-IIIc-Fc=FGFR2-IIIc-Fc>FGFR3-IIIc-Fc=FGFR1-IIIb-F>FGFR2-IIIb-Fc=FGFR4-Fc>FGFR3Fc>human IgG.

Similar experiments testing the effects of FGFR-Fc fusion proteins onviability and proliferation were performed with on the cancer cell linesU118 (FIG. 20B), U251 (FIG. 20C), SF268 (FIG. 20D), T47D (FIG. 20E) andCaki-1 (FIG. 20F). The protocols were similar to those described above,including the use of human IgG as a negative control. All of the cancercell lines tested were inhibited by one or more of the seven FGFR-Fcfusion proteins. The results are summarized in FIG. 21.

The FGFR1-IIIc-Fc mutant R1Mut4, but not R1Mut5, inhibited the viabilityand proliferation of the cancer cell lines A549 and U251 (FIG. 20G). Theassay protocol was similar to that described above. The cells weretreated with three-fold serial dilutions of FGFR1-IIIc-Fc, R1Mut4,R1Mut5, or human IgG at concentrations ranging from about 0.00457 ug/mlto about 10 ug/ml. FGFR1-IIIc-Fc, R1Mut4, and R1Mut5 were expressed in293-6E cells using the pTT5 vector as described in Example 2 andpurified as described in Example 7. Each fusion protein treatment wasperformed in triplicate wells. After five days of treatment, theviability of the A549 and U251 cells was assayed with CellTiter-Glo™Luminescent Cell Viability Assay. Each data point represents an averageof three wells. The results are shown in FIG. 20G. The A549 cells wereinhibited to a similar extent (from approximately 40 RLU to 20 RLU) byboth FGFR1-IIIc-Fc and R1Mut4 at all the doses tested. The U251 cellswere also inhibited to a similar extent by FGFR1-IIIc-Fc and by R1Mut4.They displayed dose dependence at the concentrations tested, with noinhibition observed at the lowest dose and maximal inhibition (fromapproximately 100 RLU to 30 RLU) at the highest dose.

Example 15 Sustained Expression of FGFR1-IIIc-Fc in Mice In Vivo

The effect of sustained expression of human FGFR1-IIIc-Fc fusion proteinin animal models, for example, animal tumor models, was tested using thehydrodynamic tail vein injection method to express FGFR1-IIIc-Fc inmice. Naked “mini-circle” vector cDNA encoding the FGFR1-IIIc-Fc fusionprotein was injected into three-month old C57/B16 female mice (CharlesRiver Laboratory; Hollister, Calif.). This “mini-circle” vectorcontained FGFR1 IIIc-Fc cDNA and was generated as described in Example2. The animals were injected via their tail veins using the hydrodynamictail vein injection method as reported in Liu, F. et al., Gene Therapy6:1258-1266 (1999) and U.S. Pat. No. 6,627,616, at a DNA concentrationof about 15 ug/ml in saline. About 2 ml of the DNA composition wasinjected in 5-8 seconds into each mouse. Three mice were injected withmini-circle DNA containing the FGFR1-IIIc-Fc cDNA and three mice wereinjected with saline as controls. Serum samples with a volume of about50 ul were obtained from tail vein nicks on days 2, 9, 16, 24, 30, 37,and 44 post-injection. The concentration of the FGFR1-IIIc-Fc protein inthe serum samples was analyzed by direct ELISA and the ligand bindingactivity of the FGFR1-IIIc-Fc in the mouse sera was analyzed by FGF-2competition ELISA. Both ELISA methods are described in further detailbelow.

A direct sandwich ELISA to detect FGFR1-IIIc-Fc was developed and usedto detect FGFR1-IIIc-Fc in the serum of the injected mice. Briefly,HI-BIND half-well plates (Corning; Acton, Mass.) were coated withanti-human FGFR1 antibody (QED Bioscience, San Diego, Calif.) diluted inPBS to a concentration of 3 ug/ml for 1 hr at room temperature orovernight at 4° C.; the wells were then blocked with blocking buffer(BLOTTO diluted to 3% in PBS) for 2-5 hr at room temperature. The plateswere washed with PBS containing 0.05% Tween-20, and 50 ul of mouse serumfrom each of the test animals diluted in 0.6×BLOTTO was added,respectively, to each well and incubated for 2 hr at room temperature.The plates were then washed as before and incubated with 50 ul/wellperoxidase-conjugated AffiPure goat anti-human Fc antibody (JacksonImmuno-Research Laboratories; West Grove, Pa.) diluted 1:3000 inBlocking Buffer for 60 min at room temperature. The plates were washedas before, and the wells were incubated for 10 to 20 min withreconstituted OPD solution (Sigma; Saint Louis, Mo.) at room temperatureand the absorbance at 450 nm determined.

The results are shown in FIG. 22, and demonstrate the amount ofFGFR1-IIIc-Fc fusion protein in the sera of each of the three injectedmice in the days following injection of the cDNA encoding the fusionprotein. The saline-injected mice showed no detectable levels of thefusion protein. Expression of FGFR1-IIIc-Fc in the serum remained highfor at least 44 days post-transfection in the highest expresser mouse.FGFR1-IIIc-Fc was detected at about 10 ug/ml on day 2, about 100 ug/mlon day 9, about 80 ug/ml on day 16, about 50 ug/ml on day 24, and about35 ug/ml on days 30 to 44 in this mouse. The other two mice injectedwith FGFR1-IIIc-Fc cDNA showed lower but detectable levels of the fusionprotein. This study demonstrated that high and sustained expression of ahuman FGFR1-IIIc-Fc fusion protein could be achieved in mice afterhydrodynamic tail vein injection of the cDNA and that these animalscould be used to monitor treatment with this fusion protein.

An FGF-2 competition ELISA demonstrated that the FGFR1-IIIc-Fc fusionproteins expressed in these animals was functional. FGFR1-IIIc-Fc in thesera of the above-described cDNA-injected animals was capable of bindingand sequestering a known ligand (for example, FGF-2). Briefly, serumfrom mice injected with FGFR1-IIIc-Fc cDNA was pre-treated with FGF-2and the amount of free FGF-2 remaining in the pre-treated serum measuredthe ability of the expressed FGFR1-IIIc-Fc fusion protein to bind itsligand. The amount of free FGF-2 was measured by the ability of thepre-treated serum to bind to FGFR1-IIIc immobilized on an assay plate.

The serum from the injected mice was pre-treated with FGF-2. Briefly,the serum was diluted 1/500, 1/100, and 1/20 with 0.1×BLOTTO (diluted1:10 in PBS) and added to 96-well U-bottom plates (Nunc; Rochester,N.Y.) with 200 ng/ml recombinant human FGF-2 (R&D Systems; Minneapolis,Minn.) in a volume of 50 ul for 30 min at 37° C. on a shaker, in thepresence of 20 ug/ml heparin. The pre-treatment of the serum with FGF-2sequestered the FGF-2 to the extent that the FGFR1-IIIc-Fc in the serumwas able to bind its ligand FGF-2.

The pretreated serum was then incubated with assay plates coated withFGFR1-IIIc-Fc and the binding of free FGF-2 in the serum measured. Ahigh level of free FGF-2 binding indicates that the circulatingFGFR1-IIIc-Fc was not able to bind its ligand FGF-2 and a low level offree FGF-2 binding indicates that the FGFR1-IIIc-Fc expressed in theserum of the injected mice functioned to bind its ligand FGF-2.

HI-BIND half-wells (Corning; Acton, Mass.) were coated withFGFR1-IIIc-Fc of 293-6E host cell origin, at a concentration of 5 ug/mlin PBS in a volume of 25 ul per well for 1 hr at room temperature. Thewells were blocked by adding 150 ul BLOTTO per well for 2 hr at roomtemperature. The coated half-well plates were then washed with PBScontaining 0.05% Tween-20. The washed, coated, half-well plates werethen incubated with 40 ul of the pre-treated serum for 30 min at 37° C.with shaking. The plates were washed as before with PBS containing 0.05%Tween-20. Then 2 ug/ml of biotinylated anti-FGF-2 polyclonal antibody(R&D Systems; Minneapolis, Minn.) in BLOTTO was added to each well andincubated for 30 min at 37° C. with shaking. The plates were washedagain as before and bound antibody was detected with the ABC kitaccording to manufacturer's protocol. After the final wash with PBScontaining 0.05% Tween-20, reconstituted OPD solution (Sigma; SaintLouis, Mo.) was added to each well and incubated for 10-20 min at roomtemperature and the absorbance of the wells at 450 nm determined.

Results from two control mice injected with saline and two experimentalmice injected with FGFR1-IIIc-Fc cDNA are shown in FIG. 23. Pretreatedsera from control mouse 1 and mouse 2 showed little or no inhibition ofFGF-2 binding to the FGFR1-Fc coated plates. Pretreated sera from mouse3 and mouse 4, which expressed FGFR1-IIIc-Fc, sequestered FGF-2 in adose-dependent manner, with the highest level of inhibition observedwith the most concentrated sera (1/20 dilution). FIG. 23 also shows thestandard curve of purified FGFR1-IIIc-Fc used to calculate the amount ofcirculating FGFR1-IIIc-Fc in the injected mice. The serum ofexperimental mouse 4 had the functional equivalent of 64 ug/ml ofFGFR1-IIIc-Fc and the serum of experimental mouse 3 had the functionalequivalent of 45 ug/ml serum FGFR1-IIIc-Fc.

Example 16 In Vivo Expression of R1Mut4 Via Hydrodynamic Transfection

An experiment similar to that described in Example 15 was performed byhydrodynamic transfection of R1Mut4 cDNA into mice using the minicirclevector described in Example 2. Naked “mini-circle” vector cDNA encodingR1Mut4 was injected into four month old CB17 SCID mice (Charles RiverLaboratory; Hollister, Calif.). About 2 ml of the DNA was injected at aconcentration of 20 μg/ml in 5 to 8 seconds into each of four controlmice and four R1Mut4 experimental mice. Serum samples were collected atday 2 and day 7. The concentration of R1Mut4 in the serum samples wasanalyzed by direct ELISA (see Example 15), FGF-2 competition ELISA (seeExample 15) and Western blot probing.

Results from the direct ELISA test are shown in FIG. 24. M1-M4 representsera from the four experimental R1Mut4-injected mice. Mouse 1 expressedabout 14,000 ug/ml of R1Mut4 on day 2 and about 22,000 ug/ml of R1Mut4on day 7; Mouse 2 expressed about 23,000 ug/ml of R1Mut4 on day 2 andabout 17,000 ug/ml of R1Mut4 on day 7; Mouse 3 expressed about 14,000ug/ml of R1Mut4 on day 2 and about 15,000 ug/ml of R1Mut4 on day 7; andMouse 4 expressed about 5,000 ug/ml of R1Mut4 on day 2 and about 5,000ug/ml of R1Mut4 on day 7. Thus, the concentration of R1Mut4 fusionprotein in the mouse sera ranged from about 5 mg/ml to about 22.5 mg/ml,as measured by direct ELISA. Similar results were found using the FGF-2competition ELISA and Western blot probing techniques. These resultsdemonstrated a high and sustained systemic expression of R1Mut4 byanimals injected using the hydrodynamic method, similar to that observedwith FGFR1-IIIc-Fc.

Example 17 In Vivo Comparison of FGFR1-IIIc-Fc Fusion Protein Producedby 293-6E and CHO-S Host Cells

As shown in Example 5, FGFR1-IIIc-Fc expressed by CHO-S host cellsshowed superior in vitro stability compared to FGFR1-IIIc-Fc expressedby 293-6E host cells. To determine whether FGFR1-IIIc-Fc expressed byCHO-S host cells also showed a superior in vivo stability profilecompared to FGFR1-IIIc-Fc expressed by 293-6E host cells, FGFR1-IIIc-Fcprotein from both sources was injected into mice and compared over a 72hour time course by Western blot.

C57BL6 mice were injected via tail vein with a dose of 3 mg/kilogram(kg) FGFR1-III-Fc protein purified either from CHO-S or 293-6E hostcells, as described in Examples 7 and 15. Blood was obtainedretro-orbitally at 5 min, 30 min, 24 hr, 48 hr, and 72 hr post-injectionand heparinized. Serum (100 μl) from each injected mouse and from anuninjected control mouse was separated on reducing 4-12% polyacrylamidegels via SDS-PAGE, transferred onto nitrocellulose membranes, and probedwith HRP-conjugated anti-human Fc antibody (anti-human Fc HRP) (JacksonImmunoResearch Laboratories, Inc.; West Grove, Pa.).

As shown in FIG. 26, FGFR1-IIIc-Fc purified from 293-6E cells andinjected into mice was quickly degraded in vivo and was undetectable viaWestern blot by 24 hr post-injection. FGFR1-IIIc-Fc expressed from CHO-Scells was more stable in vivo and was readily detectable in the serum,even at 72 hr post-injection. This study showed that the CHO-S hostcell-derived FGFR1-IIIc-Fc had a longer serum half life than the 293-6Ehost cell-derived material.

As also shown in FIG. 26, FGFR1-IIIc-Fc demonstrated differentelectrophoretic properties when expressed by 293-6E cells compared toCHO-S cells. FGFR1-IIIc-Fc produced by CHO-S cells had an apparentmolecular weight of approximately 90 kDa on reducing SDS-PAGE gels andmigrated to a position 3-4 kD higher than FGFR1-IIIc-Fc produced by293-6E cells. Also, the appearance of the CHO-S-derived FGFR1-IIIc-Fc inthe gel was more compact in comparison to the more diffuse gel band ofthe FGFR1-IIIc-Fc derived from 293-6E host cells.

Example 18 In Vivo Inhibition of Tumor Growth by FGFR1-IIIc-Fc andR1Mut4

Xenograft models of tumor growth can be used to assess the in vivoinhibitory properties of cancer therapeutic agents. Caki-1 human kidneytumor cells (ATCC; Manassas, Va.) form tumors when injected into severecombined immunodeficient CB17 scid/scid (CB17SCID) mice. Treatment withFGFR1-IIIc-Fc or R1Mut4 following the injection of the tumor cellsdecreases the size of the tumors which form in the mice.

Treating mice with FGFR1-IIIc-Fc via hydrodynamic tail vein transfectionfollowing the injection of Caki-1 tumor cells reduced the volume of thetumors which formed in the mice, as compared to animals mock-transfectedwith saline. Nine-week old female CB17SCID mice (Charles RiverLaboratory) were subcutaneously implanted with 1.5×10⁷ Caki-1 cells in avolume of 200 μl. On day 5 post-tumor implantation, “mini-circle”FGFR1-IIIc-Fc cDNA was delivered at a concentration of 7.5 μg/ml byhydrodynamic tail vein transfection to 13 animals, as described inExample 15. Two ml of the FGFR1-IIIc-Fc cDNA composition comprising 15μg FGFR1-IIIc-Fc cDNA was injected into the tail vein within 5-8seconds. Saline was injected into 13 control mice. The resulting tumorswere measured by caliper at days 20, 25, 29, 36, 46, 57, and 64. Thetumor volume (mm³) was calculated by the formula (π/6)*L²*W, in which L(mm) designated the length and W (mm) designated the width of the tumor.The results, shown in FIG. 25, demonstrated that FGFR1-IIIc-Fcexpression inhibited Caki-1 tumor growth by about 25% to 50% at allmeasured time points, as compared to the saline-treated controls.

Recombinant FGFR1-IIIc-Fc also reduced the volume of Caki-1 tumors inmice. FGFR1-IIIc-Fc was expressed by CHO-S host cells and purified asdescribed in Example 7. Forty eight CB17SCID mice were injectedsubcutaneously in the flank with 1.5×10⁷ human tumor Caki-1 cells in aPBS vehicle with an injection volume of 200 μl and assigned to one offour treatment groups. Group 1 (n=12) received saline only; Group 2(n=11) received 1 mg/kg FGFR1-IIIc-Fc; Group 3 (n=12) received 5 mg/kgFGFR1-IIIc-Fc; and Group 4 (n=13) received 15 mg/kg FGFR1-IIIc-Fc.Saline or FGFR1-IIIc-Fc treatment began one day after the tumors wereinjected and was given twice a week by injecting the appropriate dose ofFGFR1-IIIc-Fc into the tail vein in a volume of 200 μl with salinevehicle. Group 1 control mice received only PBS vehicle injections.

The length and width of each tumor resulting from the injected Caki-1cells were measured with a caliper and the tumor volume was calculatedusing the equation volume=(π/6)*L²*W, as described above. Measurementswere made at seven time points between day 14 and day 57 followinginjection of the Caki-1 cells. The results are shown in FIG. 30A.FGFR1-IIIc-Fc inhibited the growth of the Caki-1 cell-induced tumors byabout 50% on day 57. All three doses of FGFR1-IIIc-Fc inhibited growthto approximately the same extent.

The above experiment was also repeated using different a lower doserange of FGFR1-IIIc-Fc and a single dose of R1Mut4. The FGFR1-IIIc-Fcprotein was produced in CHO-S host cells and the R1Mut4 protein wasproduced in DG44 host cells and the proteins purified as described inExample 7.

Ninety CB17SCID mice were injected subcutaneously in the flank with1.5×10⁷ human tumor Caki-1 cells in a PBS vehicle with an injectionvolume of 200 μl and assigned to one of six treatment groups. Group 1(n=15) received saline only; Group 2 (n=15) received 5 mg/kgFGFR1-IIIc-Fc; Group 3 (n=14) received 1 mg/kg FGFR1-IIIc-Fc; Group 4(n=14) received 0.3 mg/kg FGFR1-IIIc-Fc; Group 5 (n=15) received 0.1mg/kg FGFR1-IIIc-Fc and Group 6 (n=17) received 5 mg/kg R1Mut4. Saline,FGFR1-IIIc-Fc or R1Mut4 treatment began one day after the tumors wereinjected and was given twice a week by injecting the appropriate dose ofFGFR1-IIIc-Fc into the tail vein in a volume of 200 μl with salinevehicle. Group 1 control mice received only PBS vehicle injections.

The length and width of each tumor resulting from the injected Caki-1cells were measured with a caliper and the tumor volume was calculatedusing the equation volume=(π/6)*L²*W, as described above. Measurementswere made at three time points between day 14 and day 27 followinginjection of the Caki-1 cells. The results are shown in FIG. 30B.Twice-weekly doses of 5 mg/ml of FGFR1-IIIc-Fc or R1Mut4 inhibited thegrowth of the Caki-1 cell-induced tumors by about 50% on day 27. Thisdemonstrated that the R1Mut4 fusion protein was similarly potent inpreventing tumor cell growth in vivo as the parental FGFR1-IIIc-Fcmolecule. This experiment also demonstrated that doses of FGFR1-IIIc-Fcas low as 0.3 mg/ml, but not 0.1 mg/ml, inhibited tumor cell growth in axenograft animal model.

Example 19 FGFR1-IIIc-Fc Sialylation and Glycosylation by 293-6E andCHO-S Cells

To investigate the factors responsible for the differences in stabilityof FGFR1-IIIc-Fc expressed by 293-6E cells and CHO-S cells, the sialicacid content of the two fusion proteins was compared. FGFR1-IIIc-Fcproduced by 293-6E cells had a different sialylation pattern thanFGFR1-IIIc-Fc produced from CHO-S cells.

FGFR1-IIIc-Fc expressed by 293-6E host cells, FGFR1-IIIc-Fc expressed byCHO-S host cells, and R1Mut4 expressed by CHO-S host cells were analyzedfor sialic acid content by high pH anion-exchange chromatography withpulsed amperometric detection (HPAEC-PAD) at the University ofCalifornia at San Diego. Briefly, protein was treated with 2 M HOAc at80° C. for 3 hr. Sialic acids from the samples were collected byultra-filtration through a 3,000 NMWCO membrane and eluted from a DionexCarboPac PA-1 HPAEC-PAD column (Dionex; Sunnyvale, Calif.) with a sodiumacetate gradient separating the two common forms of mammalian sialicacids, N-acetylneuraminic acid (Neu5Ac) and N-glycolylneuraminic acid(Neu5Gc).

As shown in Table 4 below, FGFR1-IIIc-Fc produced from 293-6E hostcells, and FGFR1-IIIc-Fc and R1Mut4 from CHO-S host cells aredifferentially sialated, with higher levels of both the Neu5Ac andNeu5Gc types of sialic acid present in CHO-S cell-derived proteins. Theincreased sialic acid content of CHO-S-derived FGFR1-IIIc-Fc mayaccount, in whole or in part, for the observed differences in molecularweight and in vivo stability.

TABLE 4 Sialic Acid Analysis of FGFR1-IIIc-Fc and R1Mut4 SamplenMoles/mg Protein 1111 Neu5Gc Neu5Ac Moles/Mole FGFR1-IIIc-Fc (293origin) 0.05 66.8 4.37 FGFR1-IIIc-Fc (CHO origin) 0.73 190.82 12.47R1Mut4 (CHO origin) 2.52 117.96 7.71

FIG. 27 (upper panel) shows a chromatographic analysis of the N-labeledglycans of FGFR1-IIIc-Fc expressed from 293-6E cells, following theirseparation on a Glycosep C column. FIG. 27 (lower panel) shows the sameseparation performed on FGFR1-IIIc-Fc expressed from CHO-S cells. Thechromatographic analysis was performed by Prozyme (San Leandro, Calif.).The N-labeled glycans were identified by comparison to a2-aminobenzamide (2-AB) labeled bovine fetuin N-linked glycan library.The positions of the neutral glycans, free 2-AB labeled glycans, andmono-, di-, tri-, and tetra-sialylated glycans are indicated.

FGFR1-IIIc-Fc expressed from 293-6E cells predominantly expressedneutral glycans (asialo-glycans). In contrast, FGFR1-IIIc-Fc expressedfrom CHO cells predominantly expressed negatively charged sialylatedglycans (about 86% of their carbohydrates). The negatively chargedglycans of FGFR1-IIIc-Fc expressed from 293-6E host cells were mostlymonosialylated, whereas the negatively charged glycans of FGFR1-IIIc-Fcexpressed from CHO-S host cells comprised mono-, di-, tri-, andtetra-sialylated glycans, with the tetra-sialylated glycans comprisingthe major component. These results suggest that the differences in thelevels of sialylation between FGFR1-IIIc-Fc of 293 cell origin and thatof CHO-S cell origin could be responsible for the in vivo stabilitydifferences between the two proteins, as shown in Example 18.

Example 20 Pharmacodynamic Studies of FGFR1-IIIc-Fc in Mice

Pharmacodynamic studies of FGFR1-IIIc-Fc in C57B16 mice show that thefusion protein is present in the serum for approximately 25 dayspost-injection and retains FGF-2 binding activity for approximately 14days. The studies were performed by injecting mice with a fixed dose ofrecombinant FGFR1-IIIc-Fc expressed by CHO-S cells. Nine-week old femaleC57/B16 mice (Charles River Laboratory) were injected with 200 ul ofFGFR1-IIIc-Fc protein solution at a final dose of 15 mg/kg. Serumsamples (100 ul) were collected retroorbitally at 30 min, 5 hr, and days1, 2, 3, 4, 5, 7, 14, and 25 post-injection; four mice were examined ateach time point. The concentration of FGFR1-IIIc-Fc in the serum sampleswas analyzed both by direct ELISA and FGF-2 competition ELISA, asdescribed in Example 15.

The results of the FGFR1-IIIc-Fc direct ELISA are shown in FIG. 28. Theconcentration of FGFR1-IIIc-Fc was about 62 ug/ml at 30 min, 27 ug/ml at5 hr, 21 ug/ml on day 1, 19 ug/ml on day 2, 18 ug/ml on day 3, 17 ug/mlon day 4, 18 ug/ml on day 5, 18 ug/ml on day 7, 10 ug/ml on day 14, andabout 2 ug/ml on day 25. This result showed that the recombinantFGFR1-IIIc-Fc protein was stable in mice and was detectable at leastuntil day 25 post-injection.

The results of the FGF-2 competition ELISA measuring the FGF-2 bindingcapacity of the serum FGFR1-IIIc-Fc are shown in FIG. 29. The sera wereserially diluted and the amount of binding of the FGFR1-IIIc-Fc in theserum to FGF-2 (0.2 μg/ml) was measured. As shown in FIG. 29, FGF-2binding by FGFR1-IIIc-Fc in the serum of the injected mice diminishedwith time, as seen by the rightward shift in the binding curves. FGF-2binding ability roughly paralleled the amounts of FGFR1-IIIc-Fc measuredby direct ELISA. FGF-2 binding activity remained detectable by theFGFR1-IIIc-Fc in the mouse sera at day 14 but by day 25, the competitionELISA was not able to detect FGF-2 binding activity in the amounts ofmouse serum which were tested.

Example 21 Pharmacodynamic Studies of R1Mut4 in Mice

Pharmacodynamic studies of R1Mut4 in C57 mice show that R1Mut4 hasapproximately the same in vivo stability as FGFR1-IIIc-Fc. C57 mice(Charles River Laboratory) at 2-3 months of age were injectedsubcutaneously with a dose of 10 mg/kg FGFR1-IIIc-Fc or R1Mut4 in 200 ulof saline vehicle. The FGFR1-IIIc-Fc and R1Mut4 were both prepared byexpression in a pcDNA3.1 vector in CHO-S cells, as described in Example2. Serum samples (200 ul) were collected at 4 hr, 3 days, and 7 dayspost-injection. The concentrations of the FGFR1-IIIc-Fc and R1Mut4proteins in the serum samples were analyzed by Western blot, asdescribed in Example 5 and the results shown in FIG. 31. Four hoursafter injection, mice treated with FGFR1-IIIc-Fc and R1Mut4 showed aboutthe same amount of reactivity with the anti-Fc antibody, about 6.3 ng ormore, determined by comparison with the standards of known quantities ofFGFR1-IIIc-Fc prepared from CHO-S cells and shown in the right panel. Byday 3, the amount of protein present in the serum of all the animals haddecreased to about 3.1 ng or more determined by comparison with thestandards. By day 7, the amount of protein present in the serum of allthe animals had decreased to about 1.6 ng or more. These resultsdemonstrated that recombinant FGFR1-IIIc-Fc and R1Mut4 proteins hadsimilar stability in vivo.

Example 22 Over-expression of FGFR1, FGFR3, and FGFR4 in CancerousTissues Relative to Normal Tissues

The analysis and sorting of the expression data residing in theproprietary oncology database from GeneLogic (Gaithersburg, Md.) hereinidentified cancers that over-expressed FGFR1, FGFR3, and FGFR4 comparedto corresponding normal tissues. These cancers are therapeutic targetsfor the FGFR fusion proteins of the invention. The GeneLogic databasewas generated by hybridizing Affymetrix U133 (Santa Clara, Calif.)microarray chips with cRNAs derived from over 3000 malignant tissuesamples and with cRNAs derived from over 4500 normal tissue samples. TheAffymetrix U133 microarray chip contains probes corresponding to FGFR1,probes corresponding to FGFR3, and probes corresponding to FGFR4.

Data derived from all malignant tissue samples and from all normaltissue samples were segregated into datasets corresponding to individualcancer types and to their corresponding normal tissues. Over 75 distinctcancer types are represented in the database. Cancer types with datasetscontaining samples expressing greater than the median expression valueof FGFR1 in the corresponding normal tissue dataset, greater than themedian expression value of FGFR3 in the corresponding normal tissuedataset, and greater than the median expression value of FGFR4 in thecorresponding normal tissue dataset were considered to over-expressFGFR1, to over-express FGFR3, or to over-express FGFR4, respectively.The proportion of samples in the dataset for any given cancer typeover-expressing FGFR1, FGFR3, or FGFR4 was calculated as a percentage ofthe total number of samples in that dataset, as shown in Table 5.

TABLE 5 FGFR1, FGFR2, and FGFR4 Over-expression in Malignant TissuesPercent of Malignant Tissue Samples Over-expressing FGFR1, FGFR3, orFGFR4 Cancer Type FGFR1 FGFR3 FGFR4 Leukemia B-cell acute lymphoblasticleukemia 100 Chronic myelomonocytic leukemia 100 Chronic lymphocyticleukemia 100 Chronic myeloid leukemia 75 Lymphoma Burkitt″s tumor ofextranodal site 7 Hodgkin's disease of lymph nodes 6 Malignant lymphomaof extranodal site 12 Malignant lymphoma, non-Hodgkin's type 16 1Myeloma Plasmacytoma 50 Sarcoma Malignant neoplasm of bone 83 35 3Malignant neoplasm of heart 100 Malignant neoplasm of soft tissues 37 157 Neurologic Malignant neoplasm of brain 89 21 Breast Malignant neoplasmof female breast 16 24 13 Malignant neoplasm of male breast 25 Digestivetract/Gastrointestinal Malignant neoplasm of ampulla of Vater 50 25Malignant neoplasm of appendix 50 Malignant neoplasm of colon 30 17 45Malignant neoplasm of duodenum 63 18 36 Malignant neoplasm of esophagus22 18 55 Malignant neoplasm of gallbladder 66 33 Malignant neoplasm ofliver 32 55 52 Malignant neoplasm of pancreas 11 28 14 Malignantneoplasm of the peritoneum 35 Malignant neoplasm of rectum 26 14 59Malignant neoplasm of small intestine 69 30 7 Malignant neoplasm ofstomach 30 14 28 Endocrine Cancers Malignant neoplasm of adrenal gland50 100 Malignant neoplasm of islets of Langerhans 9 45 45 Malignantneoplasm of thyroid gland 43 3 Eye Malignant neoplasm of eye 50Genitourinary Malignant neoplasm of bladder 8 56 Malignant neoplasm ofkidney 77 5 27 Malignant neoplasm of prostate 11 23 Malignant neoplasmof testis 80 100 38 Malignant neoplasm of ureter 100 GynecologicMalignant neoplasm of uterine cervix 26 52 Malignant neoplasm ofmyometrium 100 Malignant neoplasm of ovary 16 13 6 Malignant neoplasm ofuterus 60 20 Malignant neoplasm of endometrium 69 16 7 Malignantneoplasm of placenta 100 Malignant neoplasm of vulva 5 5 Head & NeckMalignant neoplasm of larynx 36 26 Malignant neoplasm of major salivarygland 66 Malignant neoplasm of nasal cavity 100 Malignant neoplasm oforal cavity 20 60 Malignant neoplasm of parotid gland 27 18 9 Malignantneoplasm of tongue 71 14 Malignant neoplasm of tonsil 100Respiratory/Thoracic Malignant neoplasm of lung 28 35 4 Malignantneoplasm of thymus 50 Malignant neoplasm of trachea 100 Skin Malignantneoplasm of skin 22 16 1

FGFR1 was over-expressed in leukemia, including B-cell acutelymphoblastic leukemia, chronic myelomonocytic leukemia, chroniclymphocytic leukemia, and chronic myeloid leukemia; in lymphoma,including Hodgkin's lymphoma, non-Hodgkin's lymphoma, and extranodallymphoma; in myeloma, including plasmacytoma; in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in neurologic cancer,including malignant neoplasms of the brain; in breast cancer, includingmalignant neoplasms of the female breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of theampulla of Vater, appendix, colon, duodenum, esophagus, liver, pancreas,peritoneum, rectum, small intestine, and stomach; in endocrine cancer,including malignant neoplasms of the adrenal gland, islets ofLangerhans, and thyroid gland; in eye cancer, including malignantneoplasms of the eye; in genitourinary cancer, including malignantneoplasms of the bladder, kidney, prostate, and testis; in gynecologiccancer, including malignant neoplasms of the uterine cervix, myometrium,ovary, uterus, endometrium, placenta, and vulva; in head and neckcancer, including malignant neoplasms of the larynx, salivary gland,nasal cavity, oral cavity, parotid gland, and tongue; inrespiratory/thoracic cancer, including malignant neoplasms of the lung,thymus, and trachea; and in skin cancer, including malignant neoplasmsof the skin (Table 5).

FGFR3 was over-expressed in lymphoma, including Burkitt's lymphoma; insarcoma, including malignant neoplasms of the bone and soft tissues; inneurologic cancer, including malignant neoplasms of the brain; in breastcancer, including malignant neoplasms of the female breast and malebreast; in digestive tract/gastrointestinal cancer, including malignantneoplasms of the ampulla of Vater, colon, duodenum, esophagus,gallbladder, liver, pancreas, rectum, small intestine, and stomach; inendocrine cancer, including malignant neoplasms of the islets ofLangerhans and thyroid gland; in genitourinary cancer, includingmalignant neoplasms of the bladder, kidney, prostate, testis, andureter; in gynecologic cancer, including malignant neoplasms of theuterine cervix, ovary, uterus, endometrium, and vulva; in head and neckcancer, including malignant neoplasms of the larynx, oral cavity,parotid gland, tongue, and tonsil; in respiratory/thoracic cancer,including malignant neoplasms of the lung; and in skin cancer, includingmalignant neoplasms of the skin (Table 5).

FGFR4 was over-expressed in lymphoma, including non-Hodgkin's lymphoma;in sarcoma, including malignant neoplasms of the bone, heart, and softtissues; in breast cancer, including malignant neoplasms of the femalebreast; in digestive tract/gastrointestinal cancer, including malignantneoplasms of the colon, duodenum, esophagus, gallbladder, liver,pancreas, rectum, small intestine, and stomach; in endocrine cancer,including malignant neoplasms of the adrenal gland and islets ofLangerhans; in genitourinary cancer, including malignant neoplasms ofthe kidney and testis; in gynecologic cancer, including malignantneoplasms of the ovary and endometrium; in head and neck cancer,including malignant neoplasms of the parotid gland; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table 5).

Table 4 identifies tumors which over-expressed more than one FGFR, forexample, malignant hyphoma, non-Hodgkin's type over-expressed FGFR1 andFGFR4; malignant neoplasm of bone, soft tissues, female breast, colon,duodenum, esophagus, liver, rectum, small intestine, stomach, islets ofLangerhans, kidney, testis, ovary, endometrium, parotid gland, lung, andskin over-expressed FGFR1, FGFR3, and FGFR4; malignant neoplasm ofbrain, ampulla of Vater, thyroid gland, bladder, prostate, uterinecervix, uterus, vulva, larynx, oral cavity, and tongue over-expressedFGFR1 and FGFR3; and malignant neoplasm of the gall bladderover-expressed FGFR3 and FGFR4.

Our analysis indicated that FGFR1, and FGFR3, and/or FGFR4 were oftenover-expressed in cancer. This over-expression implicates active FGFsignaling pathways in maintaining the viability and proliferativecapability of the affected tumors. We concluded that blocking thesesignaling pathways in the affected tumors, such as with decoy receptorslike FGFR1-Fc, FGFR3-Fc and FGFR4-Fc fusion proteins, or their variantswill reduce the viability and proliferative capacity of these tumors.

Example 23 Over-Expression of FGF-1, FGF-2, FGF-4, and FGF-5 inCancerous Tissues Relative to Normal Tissues

An analysis of the GeneLogic (Gaithersburg, Md.) database for theexpression of FGF-1, FGF-2, FGF-4, and FGF-5 in cancer tissue types andin corresponding normal tissue types was performed essentially asdescribed in Example 22. The Affymetrix U133 microarray chip containsprobes corresponding to FGF-1, FGF-2, FGF-4, and FGF-5. The proportionof samples in the dataset of any given cancer type over-expressingFGF-1, FGF-2, FGF-4, or FGF-5 was calculated as a percentage of thetotal number of samples in that dataset and is shown in Table 6. Cancerswhich over-expressed FGF-1, FGF-2, FGF-4, and FGF-5 compared tocorresponding normal tissues are therapeutic targets for the FGFR fusionproteins of the invention.

TABLE 6 FGF-1, FGF-2, FGF-4, and FGF-5 Over-expression in MalignantTissues Percent of Malignant Tissue Samples Over-expressing FGF-1,FGF-2, FGF-4, or FGF-5 Cancer Type FGF-1 FGF-2 FGF-4 FGF-5 LeukemiaAcute monocytic/monoblastic leukemia 100 Chronic lymphocytic leukemiaProlymphocytic leukemia 100 Chronic myeloid leukemia 25 LymphomaBurkitt″s tumor of extranodal site 100 Hodgkin's disease of lymph nodes20 6 Malignant lymphoma of extranodal site 12 3 3 Malignant lymphoma,non-Hodgkin's type 10 11 6 Myeloma Plasmacytoma 50 Sarcoma Malignantneoplasm of bone 29 29 3 6 Malignant neoplasm of heart 100 100 Malignantneoplasm of soft tissues 25 42 4 18 Neurologic Malignant neoplasm ofbrain 3 53 3 Breast Malignant neoplasm of female breast 19 5 7 Malignantneoplasm of male breast 50 25 Digestive tract/Gastrointestinal Malignantneoplasm of ampulla of Vater 50 25 Malignant neoplasm of appendix 50Malignant neoplasm of colon 11 12 7 Malignant neoplasm of duodenum 18Malignant neoplasm of esophagus 7 22 3 Malignant neoplasm of gallbladder33 Malignant neoplasm of liver 20 23 11 8 Malignant neoplasm of pancreas30 53 8 Malignant neoplasm of the peritoneum 7 7 7 Malignant neoplasm ofrectum 5 8 3 Malignant neoplasm of small intestine 30 53 Malignantneoplasm of stomach 19 28 9 Endocrine Cancers Malignant neoplasm ofadrenal gland 50 Malignant neoplasm of islets of Langerhans 18 63 9Malignant neoplasm of thyroid gland 22 30 7 1 Eye Malignant neoplasm ofeye Genitourinary Malignant neoplasm of bladder 8 8 4 Malignant neoplasmof kidney 2 48 6 Malignant neoplasm of prostate 8 5 4 Malignant neoplasmof testis 28 52 42 Malignant neoplasm of ureter 33 Gynecologic Malignantneoplasm of fallopian tube 33 33 Malignant neoplasm of uterine cervix 178 13 Malignant neoplasm of myometrium 11 22 11 Malignant neoplasm ofovary 12 9 6 1 Malignant neoplasm of uterus Malignant neoplasm ofendometrium 19 12 23 2 Malignant neoplasm of placenta 100 Malignantneoplasm of vulva 40 25 5 Head & Neck Malignant neoplasm of larynx 21 1015 Malignant neoplasm of major salivary gland 33 66 Malignant neoplasmof parotid gland 18 54 9 Malignant neoplasm of tongue 42 28 28 Malignantneoplasm of tonsil Respiratory/Thoracic Malignant neoplasm of lung 20 138 1 Malignant neoplasm of thymus 50 Malignant neoplasm of trachea 100Skin Malignant neoplasm of skin 27 19 3 6

FGF-1 was over-expressed in leukemia, including acutemonocytic/monoblastic leukemia and chronic myeloid leukemia; inlymphoma, including Burkitt's lymphoma, Hodgkin's lymphoma andnon-Hodgkin's lymphoma, and extranodal lymphoma; in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in neurologic cancer,including malignant neoplasms of the brain; in breast cancer, includingmalignant neoplasms of the female breast and male breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon, esophagus, gallbladder, liver, pancreas, peritoneum, rectum,small intestine, and stomach; in endocrine cancer, including malignantneoplasms of the islets of Langerhans and thyroid gland; ingenitourinary cancer, including malignant neoplasms of the bladder,kidney, prostate, testis, and ureter; in gynecologic cancer, includingmalignant neoplasms of the fallopian tube, uterine cervix, myometrium,ovary, endometrium, and vulva; in head and neck cancer, includingmalignant neoplasms of the larynx, salivary gland, parotid gland, andtongue; in respiratory/thoracic cancer, including malignant neoplasms ofthe lung; and in skin cancer, including malignant neoplasms of the skin(Table 6).

FGF-2 was over-expressed in lymphoma, including Hodgkin's lymphoma,non-Hodgkin's lymphoma, and extranodal lymphoma; in myeloma, includingplasmacytoma; in sarcoma, including malignant neoplasms of the bone,heart, and soft tissues; in neurologic cancer, including malignantneoplasms of the brain; in breast cancer, including malignant neoplasmsof the female breast; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the ampulla of Vater, appendix, colon,duodenum, esophagus, liver, pancreas, rectum, small intestine, andstomach; in endocrine cancer, including malignant neoplasms of theadrenal gland, islets of Langerhans and thyroid gland; in genitourinarycancer, including malignant neoplasms of the bladder, kidney, prostate,and testis; in gynecologic cancer, including malignant neoplasms of theuterine cervix, myometrium, ovary, endometrium, placenta, and vulva; inhead and neck cancer, including malignant neoplasms of the larynx,salivary gland, parotid gland, and tongue; in respiratory/thoraciccancer, including malignant neoplasms of the lung, thymus, and trachea;and in skin cancer, including malignant neoplasms of the skin (Table 6).

FGF-4 was over-expressed in leukemia, including pro-lymphocyticleukemia; in lymphoma, including non-Hodgkin's lymphoma and extranodallymphoma; in sarcoma, including malignant neoplasms of the bone, heart,and soft tissues; in neurologic cancer, including malignant neoplasms ofthe brain; in breast cancer, including malignant neoplasms of the femalebreast; in digestive tract/gastrointestinal cancer, including malignantneoplasms of the ampulla of Vater, colon, esophagus, liver, pancreas,peritoneum, rectum, and stomach; in endocrine cancer, includingmalignant neoplasms of the islets of Langerhans and thyroid gland; ingenitourinary cancer, including malignant neoplasms of the bladder,kidney, prostate, and testis; in gynecologic cancer, including malignantneoplasms of the fallopian tube, uterine cervix, myometrium, ovary,endometrium, and vulva; in head and neck cancer, including malignantneoplasms of the larynx and tongue; in respiratory/thoracic cancer,including malignant neoplasms of the lung; and in skin cancer, includingmalignant neoplasms of the skin (Table 6).

FGF-5 was over-expressed in sarcoma, including malignant neoplasms ofthe bone and soft tissues; in breast cancer, including malignantneoplasms of the male breast; in digestive tract/gastrointestinalcancer, including malignant neoplasms of the liver and peritoneum; inendocrine cancer, including malignant neoplasms of the thyroid gland; ingynecologic cancer, including malignant neoplasms of the ovary andendometrium; in head and neck cancer, including malignant neoplasms ofthe parotid gland; in respiratory/thoracic cancer, including malignantneoplasms of the lung; and in skin cancer, including malignant neoplasmsof the skin (Table 6).

Table 6 demonstrates that FGF-1, FGF-2, FGF-4 and FGF-5, were oftenover-expressed in cancer. This over-expression implicates active FGFsignaling pathways in maintaining viability or proliferative capabilityof the affected tumors. Blocking these signaling pathways in theaffected tumors, such as by blocking the interactions between FGF-1,FGF-2, FGF-4, and FGF-5 and their respective receptors with decoyreceptors, such as FGFR-1, FGFR3, FGFR4-Fc fusion proteins, or theirvariants will reduce the viability and proliferative capacity of thesetumors.

Example 24 Over-Expression of FGF-8, FGF-17, FGF-18, FGF-9, and FGF-20in Cancerous Tissues Relative to Normal Tissues

An analysis of the GeneLogic (Gaithersburg, Md.) database for theexpression of FGF-8, FGF-17, FGF-18, FGF-9, or FGF-20 in cancer tissuetypes and in corresponding normal tissue types was performed essentiallyas described in Example 22. The Affymetrix U133 microarray chip containsprobes corresponding to FGF-8, FGF-17, FGF-18, FGF-9, and FGF-20. Theproportion of samples in the dataset of any given cancer typeover-expressing FGF-8, FGF-17, FGF-18, FGF-9, or FGF-20 was calculatedas a percentage of the total number of samples in that dataset and isshown in Table 6. Cancers which over-expressed FGF-8, FGF-17, FGF-18,FGF-9, and FGF-20 compared to corresponding normal tissues aretherapeutic targets for the FGFR fusion proteins of the invention.

TABLE 7 FGF-8, FGF-17, FGF-18, FGF-9, and FGF-20 Over-expression inMalignant Tissues Percent of Malignant Tissue Samples Over-expressingFGF-8, FGF-17, FGF-18, FGF-9, or FGF-20 Cancer Type FGF-8 FGF-17 FGF-18FGF-9 FGF-20 Leukemia B-cell acute lymphoblastic leukemia 100 LymphomaBurkitt″s tumor of extranodal site 1 Malignant lymphoma of extranodalsite 3 Malignant lymphoma, non-Hodgkin's type 1 1 Sarcoma Malignantneoplasm of bone 6 32 Malignant neoplasm of soft tissues 2 32 16Neurologic Malignant neoplasm of brain 32 Breast Malignant neoplasm offemale breast 9 2 Malignant neoplasm of male breast 25 Digestivetract/Gastrointestinal Malignant neoplasm of ampulla of Vater 25Malignant neoplasm of appendix 50 50 Malignant neoplasm of colon 12 7 1Malignant neoplasm of esophagus 22 3 Malignant neoplasm of gallbladder66 33 Malignant neoplasm of liver 2 Malignant neoplasm of pancreas 22 2Malignant neoplasm of the peritoneum 85 35 Malignant neoplasm of rectum21 5 Malignant neoplasm of small intestine 23 Malignant neoplasm ofstomach 3 6 Endocrine Cancers Malignant neoplasm of adrenal gland 50Malignant neoplasm of islets of Langerhans 9 27 9 Malignant neoplasm ofthyroid gland 9 3 Genitourinary Malignant neoplasm of bladder 8Malignant neoplasm of kidney 7 9 Malignant neoplasm of testis 28 9Gynecologic Malignant neoplasm of fallopian tube 33 Malignant neoplasmof uterine cervix 4 17 21 Malignant neoplasm of myometrium 11 Malignantneoplasm of ovary 1 66 30 3 Malignant neoplasm of uterus 60 20 Malignantneoplasm of endometrium 66 50 12 Head & Neck Malignant neoplasm of majorsalivary gland 33 Malignant neoplasm of parotid gland 50 27 Malignantneoplasm of tongue 14 Respiratory/Thoracic Malignant neoplasm of lung 69 Malignant neoplasm of trachea 50 Skin Malignant neoplasm of skin 4 4

FGF-8 was over-expressed in endocrine cancer, including malignantneoplasms of the islets of Langerhans (Table 7).

FGF-17 was over-expressed in sarcoma, including malignant neoplasms ofthe soft tissues; and in gynecologic cancer, including malignantneoplasms of the uterine cervix and ovary (Table 7).

FGF-18 was over-expressed in lymphoma, including Hodgkin's lymphoma andextranodal lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in breast cancer, including malignant neoplasmsof the female breast and male breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of theampulla of Vater, appendix, colon, esophagus, gallbladder, liver,pancreas, peritoneum, rectum, and stomach; in endocrine cancer,including malignant neoplasms of the thyroid gland; in genitourinarycancer, including malignant neoplasms of the kidney and testis; ingynecologic cancer, including malignant neoplasms of the fallopian tube,uterine cervix, ovary, uterus, and endometrium; in head and neck cancer,including malignant neoplasms of the parotid gland; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table 7).

FGF-9 was over-expressed in leukemia, including B-cell acutelymphoblastic leukemia; in lymphoma, including Burkitt's lymphoma andnon-Hodgkin's lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in neurologic cancer, including malignantneoplasms of the brain; in breast cancer, including malignant neoplasmsof the female breast; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the appendix, colon, esophagus,gallbladder, pancreas, peritoneum, rectum, small intestine, and stomach;in endocrine cancer, including malignant neoplasms of the adrenal glandand islets of Langerhans; in genitourinary cancer, including malignantneoplasms of the bladder, kidney, and testis; in gynecologic cancer,including malignant neoplasms of the uterine cervix, myometrium, ovary,uterus, and endometrium; in head and neck cancer, including malignantneoplasms of the salivary gland, parotid gland, and tongue; inrespiratory/thoracic cancer, including malignant neoplasms of the lungand trachea; and in skin cancer, including malignant neoplasms of theskin (Table 7).

Table 6 demonstrates that FGF-8, FGF-17, FGF-18, FGF-9 and FGF-20 wereoften over-expressed in cancer. this over-expression implicates activeFGF signaling pathways in maintaining viability or proliferativecapability of the affected tumors. Blocking these signaling pathways inthe affected tumors, such as by blocking the interactions between FGF-8,FGF-17, FGF-9 and FGF-20 and their respective receptors, using decoyreceptors, such as FGFR1-Fc, FGFR3-Fc and FGFR4-Fc fusion proteins, orany of their variants will reduce the viability and proliferativecapacity of these tumors.

FGF-20 was over-expressed in digestive tract/gastrointestinal cancer,including malignant neoplasms of the colon; in endocrine cancer,including malignant neoplasms of the islets of Langerhans and thyroidgland; and in gynecologic cancer, including malignant neoplasms of theovary and endometrium (Table 7).

Example 25 Over-Expression of FGF-19, FGF-21, and FGF-23 in CancerousTissues Relative to Normal Tissues

An analysis of the GeneLogic (Gaithersburg, Md.) database for theexpression of FGF-19, FGF-21, or FGF-23 in cancer tissue types and incorresponding normal tissue types was performed essentially as describedin Example 22. The Affymetrix U133 microarray chip contains probescorresponding to FGF-19, FGF-21, and FGF-23. The proportion of samplesin the dataset of any given cancer type over-expressing FGF-19, FGF-21,or FGF-23 was calculated as a percentage of the total number of samplesin that dataset and is shown in Table 9. Cancers which over-expressedFGF-19, FGF-21, or FGF-23 compared to corresponding normal tissues aretherapeutic targets for the FGFR fusion proteins of the invention.

TABLE 8 FGF-19, FGF-21, and FGF-23 Over- expression in Malignant TissuesPercent of Malignant Tissue Samples Over-expressing FGF-19, FGF-21, orFGF-23 Cancer Type FGF-19 FGF-21 FGF-23 Sarcoma Malignant neoplasm ofbone 3 Malignant neoplasm of soft tissues 1 1 Neurologic Malignantneoplasm of brain 3 Digestive tract/Gastrointestinal Malignant neoplasmof colon 5 Malignant neoplasm of esophagus 3 Malignant neoplasm ofgallbladder 33 Malignant neoplasm of liver 11 32 Malignant neoplasm ofpancreas 22 Malignant neoplasm of rectum 7 1 Malignant neoplasm of smallintestine 7 Malignant neoplasm of stomach 1 Endocrine Cancers Malignantneoplasm of thyroid gland 3 Genitourinary Malignant neoplasm of testis19 Gynecologic Malignant neoplasm of uterine cervix 8 Malignant neoplasmof myometrium 11 Malignant neoplasm of ovary 5 Malignant neoplasm ofendometrium 12 Malignant neoplasm of vulva 5 Head & Neck Malignantneoplasm of larynx 5 Respiratory/Thoracic Malignant neoplasm of lung 5Skin Malignant neoplasm of skin 9 1

FGF-19 was over-expressed in sarcoma, including malignant neoplasms ofthe bone and soft tissues; in neurologic cancer, including malignantneoplasms of the brain; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the colon, gallbladder, liver,pancreas, rectum, small intestine, and stomach; in endocrine cancer,including malignant neoplasms of the thyroid gland; in genitourinarycancer, including malignant neoplasms of the testis; in gynecologiccancer, including malignant neoplasms of the uterine cervix, ovary,endometrium, and vulva; in head and neck cancer, including malignantneoplasms of the larynx; in respiratory/thoracic cancer, includingmalignant neoplasms of the lung; and in skin cancer, including malignantneoplasms of the skin (Table 8).

FGF-21 was over-expressed in digestive tract/gastrointestinal cancer,including malignant neoplasms of the liver and rectum (Table 8).

FGF-23 was over-expressed in sarcoma, including malignant neoplasms ofthe soft tissues; in digestive tract/gastrointestinal cancer, includingmalignant neoplasms of the esophagus; in gynecologic cancer, includingmalignant neoplasms of the myometrium; and in skin cancer, includingmalignant neoplasms of the skin (Table 8).

Table 8 demonstrates that FGF-19, FGF-21 and FGF-23 were oftenover-expressed in cancer. This over-expression implicates active FGFsignaling pathways in maintaining viability or proliferative capabilityof the affected tumors. Blocking these signaling pathways in theaffected tumors such as by blocking the interactions between FGF-19,FGF-21 and FGF-23 and their respective receptors, using decoy receptorssuch as FGFR1-Fc, FGFR3-Fc and FGFR4-Fc fusion proteins or theirvariants will reduce the viability or proliferative capacity of thesetumors.

Example 26 Over-Expression of FGFR1 and Over-Expression of FGF-1, FGF-2,FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-19, FGF-20, and FGF-21 inCancerous Tissues Relative to Normal Tissues

FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-19, FGF-20, andFGF-21 can induce proliferation in cancerous cells expressing FGFR1. Ananalysis of the GeneLogic (Gaithersburg, Md.) database for theexpression of FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-19,FGF-20, and FGF-21 in cancer tissue types and in corresponding normaltissue types was performed essentially as described in Example 22. TheAffymetrix U133 microarray chip contains probes corresponding to FGFR1,FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-19, FGF-20, andFGF-21. The proportion of samples in the dataset of any given cancertype over-expressing FGFR1, FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9,FGF-17, FGF-19, FGF-20, or FGF-21 was calculated as a percentage of thetotal number of samples in that dataset and is shown in Table 10.Cancers which over-expressed FGFR1, FGF-1, FGF-2, FGF-4, FGF-5, FGF-8,FGF-9, FGF-17, FGF-19, FGF-20, and FGF-21 compared to correspondingnormal tissues are therapeutic targets for the FGFR fusion proteins ofthe invention.

TABLE 9 FGFR-1, FGF-1, FGF-2, FGF-4, FGF-8, FGF-9, FGF-17, FGF-19,FGF-20, and FGF-21 Over-expression in Malignant Tissues Percent ofMalignant Tissue Samples Over-expressing FGFR1, FGF-1, FGF-2, FGF-4,FGF-5, FGF-8, FGF-9, FGF-17, FGF-19, FGF-20, or FGF-21 Cancer Type FGFR1FGF-1 FGF-2 FGF-4 FGF-5 FGF-8 FGF-9 FGF-17 FGF-19 FGF-20 FGF-21 LeukemiaB-cell acute lymphoblastic 100 100 leukemia Chronic myeloid leukemia 7525 Lymphoma Hodgkin's disease of lymph nodes 6 20 6 Malignant lymphomaof extranodal 12 12 3 3 site Malignant lymphoma, non-Hodgkin's 16 10 116 1 type Myeloma Plasmacytoma 50 50 Sarcoma Malignant neoplasm of bone83 29 29 3 6 32 3 Malignant neoplasm of soft tissues 37 25 42 4 18 16 21 Neurologic Malignant neoplasm of brain 89 3 53 3 32 3 Breast Malignantneoplasm of female 16 19 5 7 2 breast Digestive tract/GastrointestinalMalignant neoplasm of ampulla of 50 50 25 Vater Malignant neoplasm ofappendix 50 50 50 Malignant neoplasm of colon 30 11 12 7 7 5 1 Malignantneoplasm of duodenum 63 18 Malignant neoplasm of esophagus 22 7 22 3 3Malignant neoplasm of liver 32 20 23 11 8 11 32 Malignant neoplasm ofpancreas 11 30 53 8 2 22 Malignant neoplasm of the 35 7 7 7 35peritoneum Malignant neoplasm of rectum 26 5 8 3 5 7 1 Malignantneoplasm of small 69 30 53 23 7 intestine Malignant neoplasm of stomach30 19 28 9 6 1 Endocrine Cancers Malignant neoplasm of adrenal 50 50 50gland Malignant neoplasm of islets of 9 18 63 9 9 27 9 LangerhansMalignant neoplasm of thyroid 43 22 30 7 1 3 3 gland GenitourinaryMalignant neoplasm of bladder 8 8 8 4 8 Malignant neoplasm of kidney 772 48 6 9 Malignant neoplasm of prostate 11 8 5 4 Malignant neoplasm oftestis 80 28 52 42 9 19 Gynecologic Malignant neoplasm of uterine 26 178 13 21 4 8 cervix Malignant neoplasm of 100 11 22 11 11 myometriumMalignant neoplasm of ovary 16 12 9 6 1 30 1 5 3 Malignant neoplasm ofuterus 60 20 Malignant neoplasm of 69 19 12 23 2 50 12 12 endometriumMalignant neoplasm of placenta 100 100 Malignant neoplasm of vulva 5 4025 5 5 Head & Neck Malignant neoplasm of larynx 36 21 10 15 5 Malignantneoplasm of major 66 33 66 33 salivary gland Malignant neoplasm ofparotid 27 18 54 9 27 gland Malignant neoplasm of tongue 71 42 28 28 14Respiratory/Thoracic Malignant neoplasm of lung 28 20 13 8 1 9 5Malignant neoplasm of thymus 50 50 Malignant neoplasm of trachea 100 10050 Skin Malignant neoplasm of skin 22 27 19 3 6 4 9

FGFR1 and FGF-1 were both over-expressed in leukemia, including chronicmyeloid leukemia; in lymphoma, including Hodgkin's lymphoma,non-Hodgkin's lymphoma, and extranodal lymphoma; in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in neurologic cancer,including malignant neoplasms of the brain; in breast cancer, includingmalignant neoplasms of the female breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon, esophagus, liver, pancreas, peritoneum, rectum, small intestine,and stomach; in endocrine cancer, including malignant neoplasms of theislets of Langerhans, and thyroid gland; in genitourinary cancer,including malignant neoplasms of the bladder, kidney, prostate, andtestis; in gynecologic cancer, including malignant neoplasms of theuterine cervix, myometrium, ovary, endometrium, and vulva; in head andneck cancer, including malignant neoplasms of the larynx, salivarygland, parotid gland, and tongue; in respiratory/thoracic cancer,including malignant neoplasms of the lung; and in skin cancer, includingmalignant neoplasms of the skin (Table 9).

FGFR1 and FGF-2 were both over-expressed in lymphoma, includingHodgkin's lymphoma, non-Hodgkin's lymphoma, and extranodal lymphoma; inmyeloma, including plasmacytoma; in sarcoma, including malignantneoplasms of the bone and soft tissues; in neurologic cancer, includingmalignant neoplasms of the brain; in breast cancer, including malignantneoplasms of the female breast; in digestive tract/gastrointestinalcancer, including malignant neoplasms of the ampulla of Vater, appendix,colon, duodenum, esophagus, liver, pancreas, rectum, small intestine,and stomach; in endocrine cancer, including malignant neoplasms of theadrenal gland, islets of Langerhans, and thyroid gland; in genitourinarycancer, including malignant neoplasms of the bladder, kidney, prostate,and testis; in gynecologic cancer, including malignant neoplasms of theuterine cervix, myometrium, ovary, endometrium, placenta, and vulva; inhead and neck cancer, including malignant neoplasms of the larynx,salivary gland, parotid gland, and tongue; in respiratory/thoraciccancer, including malignant neoplasms of the lung, thymus, and trachea;and in skin cancer, including malignant neoplasms of the skin (Table 9).

FGFR1 and FGF-4 were both over-expressed in lymphoma, includingnon-Hodgkin's lymphoma, and extranodal lymphoma; in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in neurologic cancer,including malignant neoplasms of the brain; in breast cancer, includingmalignant neoplasms of the female breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of theampulla of Vater, colon, esophagus, liver, pancreas, peritoneum, rectum,and stomach; in endocrine cancer, including malignant neoplasms of theislets of Langerhans, and thyroid gland; in genitourinary cancer,including malignant neoplasms of the bladder, kidney, prostate, andtestis; in gynecologic cancer, including malignant neoplasms of theuterine cervix, myometrium, ovary, endometrium, and vulva; in head andneck cancer, including malignant neoplasms of the larynx and tongue; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table 9).

FGFR1 and FGF-5 were both over-expressed in sarcoma, including malignantneoplasms of the bone and soft tissues; in digestivetract/gastrointestinal cancer, including malignant neoplasms of theliver and peritoneum; in endocrine cancer, including malignant neoplasmsof the thyroid gland; in gynecologic cancer, including malignantneoplasms of the ovary and endometrium; in head and neck cancer,including malignant neoplasms of the parotid gland; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table 9).

FGFR1 and FGF-8 were both over-expressed in endocrine cancer, includingmalignant neoplasms of the islets of Langerhans (Table 9).

FGFR1 and FGF-9 were both over-expressed in leukemia, including B-cellacute lymphoblastic leukemia; in lymphoma, including non-Hodgkin'slymphoma; in sarcoma, including malignant neoplasms of the bone and softtissues; in neurologic cancer, including malignant neoplasms of thebrain; in breast cancer, including malignant neoplasms of the femalebreast; in digestive tract/gastrointestinal cancer, including malignantneoplasms of the appendix, colon, esophagus, pancreas, peritoneum,rectum, small intestine, and stomach; in endocrine cancer, includingmalignant neoplasms of the adrenal gland and islets of Langerhans; ingenitourinary cancer, including malignant neoplasms of the bladder,kidney, and testis; in gynecologic cancer, including malignant neoplasmsof the uterine cervix, myometrium, ovary, uterus, and endometrium; inhead and neck cancer, including malignant neoplasms of the salivarygland, parotid gland, and tongue; in respiratory/thoracic cancer,including malignant neoplasms of the lung and trachea; and in skincancer, including malignant neoplasms of the skin (Table 9).

FGFR1 and FGF-17 were both over-expressed in sarcoma, includingmalignant neoplasms of the soft tissues; and in gynecologic cancer,including malignant neoplasms of the uterine cervix and ovary (Table 9).

FGFR1 and FGF-19 were both over-expressed in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in neurologic cancer,including malignant neoplasms of the brain; in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon, liver, pancreas, rectum, small intestine, and stomach; inendocrine cancer, including malignant neoplasms of the thyroid gland; ingenitourinary cancer, including malignant neoplasms of the testis; ingynecologic cancer, including malignant neoplasms of the uterine cervix,ovary, endometrium, and vulva; in head and neck cancer, includingmalignant neoplasms of the larynx; in respiratory/thoracic cancer,including malignant neoplasms of the lung; and in skin cancer, includingmalignant neoplasms of the skin (Table 9).

FGFR1 and FGF-20 were both over-expressed in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon; in endocrine cancer, including malignant neoplasms of the isletsof Langerhans, and thyroid gland; and in gynecologic cancer, includingmalignant neoplasms of the ovary and endometrium (Table 9).

FGFR1 and FGF-21 were both over-expressed in digestivetract/gastrointestinal cancer, including malignant neoplasms of theliver and rectum (Table 9).

Table 9 demonstrates that FGFR1 and any one or more of FGF-1, FGF-2,FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-19, FGF-20 and FGF-21 were oftenover-expressed in cancer. This over-expression implicates active FGFsignaling pathways in maintaining viability or proliferative capabilityof the affected tumors. Blocking these signaling pathways in theaffected tumors, such as by blocking the interaction between FGF-1,FGF-2, FGF-4, FGF-5, FGF-8, FGF-0, FGF-17, FGF-19 and/or FGF-20 andtheir respective receptors and between FGFR1 and its binding ligands,using decoy receptors such as FGFR1-Fc, FGFR3-Fc, and FGFR4-Fc fusionproteins, or their variants will reduce the viability or proliferativecapacity of these tumors.

Example 27 Over-Expression of FGFR3 and Over-Expression of FGF-1, FGF-2,FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, and FGF-20 inCancerous Tissues Relative to Normal Tissues

FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, andFGF-20 can induce proliferation in cancerous cells expressing FGFR3. Ananalysis of the GeneLogic (Gaithersburg, Md.) database for theexpression of FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18,FGF-19, and FGF-20 in cancer tissue types and in corresponding normaltissue types was performed essentially as described in Example 22. TheAffymetrix U133 microarray chip contains probes corresponding to FGFR3,FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, andFGF-20. The proportion of samples in the dataset of any given cancertype over-expressing FGFR3, FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9,FGF-17, FGF-18, FGF-19, and FGF-20 was calculated as a percentage of thetotal number of samples in that dataset and is shown in Table 11.Cancers which over-expressed FGFR3, FGF-1, FGF-2, FGF-4, FGF-5, FGF-8,FGF-9, FGF-17, FGF-18, FGF-19, and FGF-20 compared to correspondingnormal tissues are therapeutic targets for the FGFR fusion proteins ofthe invention.

TABLE 10 FGFR-3, FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17,FGF-18, FGF-19, and FGF-20 Over-expression in Malignant Tissues Percentof Malignant Tissue Samples Over-expressing FGFR3, FGF-1, FGF-2, FGF-4,FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, or FGF-20 Cancer Type FGFR3FGF-1 FGF-2 FGF-4 FGF-5 FGF-8 FGF-9 FGF-17 FGF-18 FGF-19 FGF-20 LymphomaBurkitt's tumor of extranodal site 7 100 1 Sarcoma Malignant neoplasm ofbone 35 29 29 3 6 32 6 3 Malignant neoplasm of soft tissues 15 25 42 418 16 2 32 1 Neurologic Malignant neoplasm of brain 21 3 53 3 32 3Breast Malignant neoplasm of female 24 19 5 7 2 9 breast Malignantneoplasm of male breast 25 50 25 25 Digestive tract/GastrointestinalMalignant neoplasm of ampulla of 25 50 25 25 Vater Malignant neoplasm ofcolon 17 11 12 7 7 12 5 1 Malignant neoplasm of duodenum 18 18 Malignantneoplasm of esophagus 18 7 22 3 3 22 Malignant neoplasm of gallbladder66 33 33 66 33 Malignant neoplasm of liver 55 20 23 11 8 2 11 Malignantneoplasm of pancreas 28 30 53 8 2 22 22 Malignant neoplasm of rectum 145 8 3 5 21 7 Malignant neoplasm of small 30 30 53 23 7 intestineMalignant neoplasm of stomach 14 19 28 9 6 3 1 Endocrine CancersMalignant neoplasm of islets of 45 18 63 9 9 27 9 Langerhans Malignantneoplasm of thyroid 3 22 30 7 1 9 3 3 gland Genitourinary Malignantneoplasm of bladder 56 8 8 4 8 Malignant neoplasm of kidney 5 2 48 6 9 7Malignant neoplasm of prostate 23 8 5 4 Malignant neoplasm of testis 10028 52 42 9 28 19 Malignant neoplasm of ureter 100 33 GynecologicMalignant neoplasm of uterine 52 17 8 13 21 4 17 8 cervix Malignantneoplasm of ovary 13 12 9 6 1 30 1 66 5 3 Malignant neoplasm of uterus20 20 60 Malignant neoplasm of 16 19 12 23 2 50 66 12 12 endometriumMalignant neoplasm of vulva 5 40 25 5 5 Head & Neck Malignant neoplasmof larynx 26 21 10 15 5 Malignant neoplasm of parotid 18 18 54 9 27 50gland Malignant neoplasm of tongue 14 42 28 28 14 Respiratory/ThoracicMalignant neoplasm of lung 35 20 13 8 1 9 6 5 Skin Malignant neoplasm ofskin 16 27 19 3 6 4 4 9

FGFR3 and FGF-1 were both over-expressed in lymphoma, includingBurkitt's lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in neurologic cancer, including malignantneoplasms of the brain; in breast cancer, including malignant neoplasmsof the female breast and male breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon, esophagus, gallbladder, liver, pancreas, rectum, small intestine,and stomach; in endocrine cancer, including malignant neoplasms of theislets of Langerhans and thyroid gland; in genitourinary cancer,including malignant neoplasms of the bladder, kidney, prostate, testis,and ureter; in gynecologic cancer, including malignant neoplasms of theuterine cervix, ovary, endometrium, and vulva; in head and neck cancer,including malignant neoplasms of the larynx, parotid gland, and tongue;in respiratory/thoracic cancer, including malignant neoplasms of thelung; and in skin cancer, including malignant neoplasms of the skin(Table 10).

FGFR3 and FGF-2 were both over-expressed in sarcoma, including malignantneoplasms of the bone and soft tissues; in neurologic cancer, includingmalignant neoplasms of the brain; in breast cancer, including malignantneoplasms of the female breast; in digestive tract/gastrointestinalcancer, including malignant neoplasms of the ampulla of Vater, colon,duodenum, esophagus, liver, pancreas, rectum, small intestine, andstomach; in endocrine cancer, including malignant neoplasms of theislets of Langerhans and thyroid gland; in genitourinary cancer,including malignant neoplasms of the bladder, kidney, prostate, andtestis; in gynecologic cancer, including malignant neoplasms of theuterine cervix, ovary, endometrium, and vulva; in head and neck cancer,including malignant neoplasms of the larynx, parotid gland, and tongue;in respiratory/thoracic cancer, including malignant neoplasms of thelung; and in skin cancer, including malignant neoplasms of the skin(Table 10).

FGFR3 and FGF-4 were both over-expressed in sarcoma, including malignantneoplasms of the bone and soft tissues; in neurologic cancer, includingmalignant neoplasms of the brain; in breast cancer, including malignantneoplasms of the female breast; in digestive tract/gastrointestinalcancer, including malignant neoplasms of the ampulla of Vater, colon,esophagus, liver, pancreas, rectum, and stomach; in endocrine cancer,including malignant neoplasms of the islets of Langerhans and thyroidgland; in genitourinary cancer, including malignant neoplasms of thebladder, kidney, prostate, and testis; in gynecologic cancer, includingmalignant neoplasms of the uterine cervix, ovary, endometrium, andvulva; in head and neck cancer, including malignant neoplasms of thelarynx and tongue; in respiratory/thoracic cancer, including malignantneoplasms of the lung; and in skin cancer, including malignant neoplasmsof the skin (Table 10).

FGFR3 and FGF-5 were both over-expressed in sarcoma, including malignantneoplasms of the bone and soft tissues; in breast cancer, includingmalignant neoplasms of the male breast; in digestivetract/gastrointestinal cancer, including malignant neoplasms of theliver; in endocrine cancer, including malignant neoplasms of the thyroidgland; in gynecologic cancer, including malignant neoplasms of the ovaryand endometrium; in head and neck cancer, including malignant neoplasmsof the parotid gland; in respiratory/thoracic cancer, includingmalignant neoplasms of the lung; and in skin cancer, including malignantneoplasms of the skin (Table 10).

FGFR3 and FGF-8 were both over-expressed in endocrine cancer, includingmalignant neoplasms of the islets of Langerhans (Table 10).

FGFR3 and FGF-9 were both over-expressed in lymphoma, includingBurkitt's lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in neurologic cancer, including malignantneoplasms of the brain; in breast cancer, including malignant neoplasmsof the female breast; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the colon, esophagus, gallbladder,pancreas, rectum, small intestine, and stomach; in endocrine cancer,including malignant neoplasms of the islets of Langerhans; ingenitourinary cancer, including malignant neoplasms of the bladder,kidney, and testis; in gynecologic cancer, including malignant neoplasmsof the uterine cervix, ovary, uterus, and endometrium; in head and neckcancer, including malignant neoplasms of the parotid gland and tongue;in respiratory/thoracic cancer, including malignant neoplasms of thelung; and in skin cancer, including malignant neoplasms of the skin(Table 10).

FGFR3 and FGF-17 were both over-expressed in sarcoma, includingmalignant neoplasms of the soft tissues, and in gynecologic cancer,including malignant neoplasms of the uterine cervix and ovary (Table10).

FGFR3 and FGF-18 were both over-expressed in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in breast cancer,including malignant neoplasms of the female breast and male breast; indigestive tract/gastrointestinal cancer, including malignant neoplasmsof the ampulla of Vater, colon, esophagus, gallbladder, liver, pancreas,rectum, and stomach; in endocrine cancer, including malignant neoplasmsof the thyroid gland; in genitourinary cancer, including malignantneoplasms of the kidney and testis; in gynecologic cancer, includingmalignant neoplasms of the uterine cervix, ovary, uterus, andendometrium; in head and neck cancer, including malignant neoplasms ofthe parotid gland; in respiratory/thoracic cancer, including malignantneoplasms of the lung; and in skin cancer, including malignant neoplasmsof the skin (Table 10).

FGFR3 and FGF-19 were both over-expressed in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in neurologic cancer,including malignant neoplasms of the brain; in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon; gallbladder, liver, pancreas, rectum, small intestine, andstomach; in endocrine cancer, including malignant neoplasms of thethyroid gland; in genitourinary cancer, including malignant neoplasms ofthe testis; in gynecologic cancer, including malignant neoplasms of theuterine cervix, ovary, endometrium, and vulva; in head and neck cancer,including malignant neoplasms of the larynx; in respiratory/thoraciccancer, including malignant neoplasms of the lung; and in skin cancer,including malignant neoplasms of the skin (Table 10).

FGFR3 and FGF-20 were both over-expressed in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon; in endocrine cancer, including malignant neoplasms of the isletsof Langerhans and thyroid gland; and in gynecologic cancer, includingmalignant neoplasms of the ovary and endometrium (Table 10).

Table 11 demonstrates that FGFR3 and any one or more of FGF-1, FGF-2,FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19 and FGF-20 were oftenover-expressed in cancer. This over-expression implicates active FGFsignaling pathways in maintaining viability or proliferative capacity ofthe affected tumors. Blocking these signaling pathways in the affectedtumors, such as by blocking the interactions between FGF-1, FGF-2,FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19 and/or FGF-20 andtheir respective receptors and between FGFR3 and its binding ligandswith decoy receptors such as FGFR1-Fc, FGFR3-Fc and FGFR4-Fc fusionproteins, or their variants will reduce the viability or proliferativecapacity of these tumors.

Example 28 Over-Expression of FGFR4 and Over-Expression of FGF-1, FGF-2,FGF-4, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21, and FGF-23in Cancerous Tissues Relative to Normal Tissues

FGF-1, FGF-2, FGF-4, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, FGF-20,FGF-21, and FGF-23 can induce proliferation in cancerous cellsexpressing FGFR4. An analysis of the GeneLogic (Gaithersburg, Md.)database for the expression of FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9,FGF-17, FGF-18, FGF-19, and FGF-20 in cancer tissue types and incorresponding normal tissue types was performed essentially as describedin Example 22. The Affymetrix U133 microarray chip contains probescorresponding to FGFR3, FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9,FGF-17, FGF-18, FGF-19, and FGF-20. The proportion of samples in thedataset of any given cancer type over-expressing FGFR3, FGF-1, FGF-2,FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, and FGF-20 wascalculated as a percentage of the total number of samples in thatdataset and is shown in Table 11. Cancers which over-expressed FGFR3,FGF-1, FGF-2, FGF-4, FGF-5, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, andFGF-20 compared to corresponding normal tissues are therapeutic targetsfor the FGFR fusion proteins of the invention.

TABLE 11 FGFR-4, FGF-1, FGF-2, FGF-4, FGF-8, FGF-9, FGF-17, FGF-18,FGF-19, FGF-20, FGF-21, and FGF-23 Over-expression in Malignant TissuesPercent of Malignant Tissue Samples Over-expressing FGFR4, FGF-1, FGF-2,FGF-4, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21, or FGF-23Cancer Type FGFR4 FGF-1 FGF-2 FGF-4 FGF-8 FGF-9 FGF-17 FGF-18 FGF-19FG-20 FGF-21 FGF-23 Lymphoma Malignant lymphoma, non- 1 10 11 6 1 1Hodgkin's type Sarcoma Malignant neoplasm of bone 3 29 29 3 32 6 3Malignant neoplasm of heart 100 100 100 Malignant neoplasm of soft 7 2542 4 16 2 32 1 1 tissues Breast Malignant neoplasm of female 13 19 5 7 29 breast Digestive tract/Gastrointestinal Malignant neoplasm of colon 4511 12 7 7 12 5 1 Malignant neoplasm of 36 18 duodenum Malignant neoplasmof 55 7 22 3 3 22 3 esophagus Malignant neoplasm of 33 33 33 66 33gallbladder Malignant neoplasm of liver 52 20 23 11 2 11 32 Malignantneoplasm of pancreas 14 30 53 8 2 22 22 Malignant neoplasm of rectum 595 8 3 5 21 7 1 Malignant neoplasm of small 7 30 53 23 7 intestineMalignant neoplasm of stomach 28 19 28 9 6 3 1 Endocrine CancersMalignant neoplasm of adrenal 100 50 50 gland Malignant neoplasm ofislets of 45 18 63 9 9 27 9 Langerhans Genitourinary Malignant neoplasmof kidney 27 2 48 6 9 7 Malignant neoplasm of testis 38 28 52 42 9 28 19Gynecologic Malignant neoplasm of ovary 6 12 9 6 30 1 66 5 3 Malignantneoplasm of 7 19 12 23 50 66 12 12 endometrium Head & Neck Malignantneoplasm of parotid 9 18 54 27 50 gland Respiratory/Thoracic Malignantneoplasm of lung 4 20 13 8 9 6 5 Skin Malignant neoplasm of skin 1 27 193 4 4 9 1

FGFR4 and FGF-1 were both over-expressed in lymphoma, includingnon-Hodgkin's lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in breast cancer, including malignant neoplasmsof the female breast; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the colon, esophagus, gallbladder,liver, pancreas, rectum, small intestine, and stomach; in endocrinecancer, including malignant neoplasms of the islets of Langerhans; ingenitourinary cancer, including malignant neoplasms of the kidney andtestis; in gynecologic cancer, including malignant neoplasms of theovary and endometrium; in head and neck cancer, including malignantneoplasms of the parotid gland; in respiratory/thoracic cancer,including malignant neoplasms of the lung; and in skin cancer, includingmalignant neoplasms of the skin (Table 11).

FGFR4 and FGF-2 were both over-expressed in lymphoma, includingnon-Hodgkin's lymphoma; in sarcoma, including malignant neoplasms of thebone, heart, and soft tissues; in breast cancer, including malignantneoplasms of the female breast; in digestive tract/gastrointestinalcancer, including malignant neoplasms of the colon, duodenum, esophagus,liver, pancreas, rectum, small intestine, and stomach; in endocrinecancer, including malignant neoplasms of the adrenal gland and islets ofLangerhans; in genitourinary cancer, including malignant neoplasms ofthe kidney and testis; in gynecologic cancer, including malignantneoplasms of the ovary and endometrium; in head and neck cancer,including malignant neoplasms of the parotid gland; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table11).

FGFR4 and FGF-4 were both over-expressed in lymphoma, includingnon-Hodgkin's lymphoma; in sarcoma, including malignant neoplasms of thebone, heart, and soft tissues; in breast cancer, including malignantneoplasms of the female breast; in digestive tract/gastrointestinalcancer, including malignant neoplasms of the colon; esophagus, liver,pancreas, rectum, and stomach; in endocrine cancer, including malignantneoplasms of the islets of Langerhans; in genitourinary cancer,including malignant neoplasms of the kidney and testis; in gynecologiccancer, including malignant neoplasms of the ovary and endometrium; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table11).

FGFR4 and FGF-8 were both over-expressed in endocrine cancer, includingmalignant neoplasms of the islets of Langerhans (Table 12).

FGFR4 and FGF-9 were both over-expressed in lymphoma, includingnon-Hodgkin's lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in breast cancer, including malignant neoplasmsof the female breast; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the colon, esophagus, gallbladder,pancreas, rectum, small intestine, and stomach; in endocrine cancer,including malignant neoplasms of the adrenal gland and islets ofLangerhans; in genitourinary cancer, including malignant neoplasms ofthe kidney and testis; in gynecologic cancer, including malignantneoplasms of the ovary and endometrium; in head and neck cancer,including malignant neoplasms of the parotid gland; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table11).

FGFR4 and FGF-17 were both over-expressed in sarcoma, includingmalignant neoplasms of the soft tissues; and in gynecologic cancer,including malignant neoplasms of the ovary (Table 11).

FGFR4 and FGF-18 were both over-expressed in lymphoma, includingnon-Hodgkin's lymphoma; in sarcoma, including malignant neoplasms of thebone and soft tissues; in breast cancer, including malignant neoplasmsof the female breast; in digestive tract/gastrointestinal cancer,including malignant neoplasms of the colon, esophagus, gallbladder,liver, pancreas, rectum, and stomach; in genitourinary cancer, includingmalignant neoplasms of the kidney and testis; in gynecologic cancer,including malignant neoplasms of the ovary and endometrium; in head andneck cancer, including malignant neoplasms of the parotid gland; inrespiratory/thoracic cancer, including malignant neoplasms of the lung;and in skin cancer, including malignant neoplasms of the skin (Table11).

FGFR4 and FGF-19 were both over-expressed in sarcoma, includingmalignant neoplasms of the bone and soft tissues; in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon, gallbladder, liver, pancreas, rectum, small intestine, andstomach; in genitourinary cancer, including malignant neoplasms of thetestis; in gynecologic cancer, including malignant neoplasms of theovary and endometrium; in respiratory/thoracic cancer, includingmalignant neoplasms of the lung; and in skin cancer, including malignantneoplasms of the skin (Table 11).

FGFR4 and FGF-20 were both over-expressed in digestivetract/gastrointestinal cancer, including malignant neoplasms of thecolon; in endocrine cancer, including malignant neoplasms of the isletsof Langerhans; and in gynecologic cancer, including malignant neoplasmsof the ovary and endometrium (Table 11).

FGFR4 and FGF-21 were both over-expressed in digestivetract/gastrointestinal cancer, including malignant neoplasms of theliver and rectum (Table 11).

FGFR4 and FGF-23 were both over-expressed in sarcoma, includingmalignant neoplasms of the soft tissues; in digestivetract/gastrointestinal cancer, including malignant neoplasms of theesophagus; and in skin cancer, including malignant neoplasms of the skin(Table 11).

This analysis demonstrated that FGFR4, FGF-1, FGF-2, FGF-4, FGF-5,FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21 and FGF-23 arecommonly over-expressed in cancer. This over-expression implicatesactive FGF signaling pathways in maintaining viability and/orproliferative capability of the affected tumors. Blocking these FGFRsignaling pathways in the affected tumors, such as with FGFR1-Fc,FGFR3-Fc, or FGFR4-Fc fusion proteins, will reduce the viability and/orproliferative capacity of these tumors.

Table 11 demonstrates that FGFR4 and any of FGF-1, FGF-2, FGF-4, FGF-5,FGF-8, FGF-9, FGF, FGF-17, FGF-18, FGF-19, FGF-20, FGF-21 and FGF-23were often over-expressed in cancer. This over-expression implicatesactive FGF signaling pathways in maintaining viability or proliferativecapability of the affected tumors. blocking these signaling pathways inthe affected tumors, such as by blocking the interactions between FGF-1,FGF-2, FGF-4, FGF-8, FGF-9, FGF-17, FGF-18, FGF-19, FGF-20 and FGF-23;and between FGFR4 and its binding ligands with decoy receptors such asFGFR1-Fc, FGFR3-Fc and FGFR4-Fc fusion proteins, or their variants, willreduce the viability or proliferative capacity of these tumors.

INDUSTRIAL APPLICABILITY

The FGFR fusion proteins and the polynucleotide molecules that encodethem are useful in treating proliferative diseases and diseasesinvolving angiogenesis, including cancer. They can be used to diagnose,prevent, and treat these diseases.

SEQUENCE LISTING

A Sequence Listing is provided both in paper format and in computerreadable form. It is accompanied by a transmittal sheet.

HG1020122N1 NP_056934_1-374 SEQ.ID.NO. 1ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAG HG1020123N1 NP_075594_1-285SEQ.ID.NO. 2ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAG HG1020124N1 NP_000595_1-376 SEQ.ID.NO. 3ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGHG1021602N1 NP_056934_1-374_GS_17939658_ 233-464_C237S SEQ.ID.NO. 4ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGggatccGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020125N1 NP_056934_1-374_17939658_233-464_C237S SEQ.ID.NO. 5ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020127N1 NP_056934_1-370_17939658_ 233-464_C237SSEQ.ID.NO. 6ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAAHG1020126N1 NP_056934_1-366_17939658_ 233-464_C237S SEQ.ID.NO. 7ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020128N1 NP_056934_1-365_17939658_ 233-464_C237S SEQ.ID.NO. 8ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020129N1 NP_056934_1-360_17939658_ 233-464_C237S SEQ.ID.NO. 9ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020130N1 NP_056934_1-355_17939658_ 233-464_C237S SEQ.ID.NO. 10ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020131N1 NP_056934_1-374_D364-D365_17939658_233-464_C237S SEQ.ID.NO. 11ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020133N1 NP_056934_1-374_P364M_17939658_ 233-464_C237SSEQ.ID.NO. 12ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020134N1 NP_056934_1-374_M367N_17939658_233-464_C237S SEQ.ID.NO. 13ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGaacACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020132N1 NP_056934_1-374_P364G_17939658_233-464_C237S SEQ.ID.NO. 14ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020135N1 NP_056934_1-374_P364M_M367N_17939658_233-464_C237S SEQ.ID.NO. 15ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGaacACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020136N1 NP_075594_1-285_17939658_ 233-464_C237SSEQ.ID.NO. 16ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020138N1 NP_075594_1-281_17939658_ 233-464_C237S SEQ.ID.NO. 17ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020137N1 NP_075594_1-277_17939658_ 233-464_C237S SEQ.ID.NO. 18ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020139N1 NP_075594_1-276_17939658_233-464_C237S SEQ.ID.NO. 19ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020140N1 NP_075594_1-271_17939658_233-464_C237S SEQ.ID.NO. 20ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAAHG1020141N1 NP_075594_1-285_D275-D276_ 17939658_233-464_C237SSEQ.ID.NO. 21ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020143N1 NP_075594_1-285_P275M_17939658_ 233-464_C237S SEQ.ID.NO. 22ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020144N1 NP_075594_1-285_M278N_17939658_ 233-464_C237S SEQ.ID.NO. 23ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGaacACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020142N1 NP_075594_1-285_P275G_17939658_ 233-464_C237S SEQ.ID.NO. 24ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020145N1 NP_075594_1-285_P275M_M278N_ 17939658_233-464_C237SSEQ.ID.NO. 25ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGaacACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020146N1 NP_000595_1-376_17939658_ 233-464_C237S SEQ.ID.NO. 26ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020148N1 NP_000595_1-372_17939658_233-464_C237S SEQ.ID.NO. 27ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020147N1 NP_000595_1-368_17939658_ 233-464_C237SSEQ.ID.NO. 28ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020149N1 NP_000595_1-367_17939658_ 233-464_C237S SEQ.ID.NO. 29ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020150N1 NP_000595_1-362_17939658_ 233-464_C237S SEQ.ID.NO. 30ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1020151N1 NP_000595_1-376_D366-D367_ 17939658_233-464_C237SSEQ.ID.NO. 31ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020153N1 NP_000595_1-376_P366M_17939658_233-464_C237S SEQ.ID.NO. 32ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020154N1 NP_000595_1-376_M369N_17939658_233-464_C237S SEQ.ID.NO. 33ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGaacACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020152N1 NP_000595_1-376_P366G_17939658_233-464_C237S SEQ.ID.NO. 34ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020155N1 NP_000595_1-376_P366M_M369N_17939658_233-464_C237S SEQ.ID.NO. 35ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGaacACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020157N1 NP_056934_1-370 SEQ.ID.NO. 36ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCC HG1020156N1 NP_056934_1-366 SEQ.ID.NO. 37ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTG HG1020158N1 NP_056934_1-365 SEQ.ID.NO. 38ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCA HG1020159N1 NP_056934_1-360 SEQ.ID.NO. 39ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGHG1020160N1 NP_056934_1-355 SEQ.ID.NO. 40ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCHG1020161N1 NP_056934_1-374_D364-D365 SEQ.ID.NO. 41ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGGTGATGACCTCGCCCCTGTACCTGGAG HG1020163N1 NP_056934_1-374_P364MSEQ.ID.NO. 42ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGATGACCTCGCCCCTGTACCTGGAGHG1020164N1 NP_056934_1-374_M367N SEQ.ID.NO. 43ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGaacACCTCGCCCCTGTACCTGGAGHG1020162N1 NP_056934_1-374_P364G SEQ.ID.NO. 44ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGATGACCTCGCCCCTGTACCTGGAGHG1020165N1 NP_056934_1-374_P364M_M367N SEQ.ID.NO. 45ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGaacACCTCGCCCCTGTACCTGGAG HG1020167N1 NP_075594_1-281SEQ.ID.NO. 46ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCG CCCHG1020166N1 NP_075594_1-277 SEQ.ID.NO. 47ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGHG1020168N1 NP_075594_1-276 SEQ.ID.NO. 48ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAHG1020169N1 NP_075594_1-271 SEQ.ID.NO. 49ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTG HG1020170N1 NP_075594_1-285_D275-D276SEQ.ID.NO. 50ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGGTGATGACCTCGCCCCTG TACCTGGAGHG1020172N1 NP_075594_1-285_P275M SEQ.ID.NO. 51ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGATGACCTCGCCCCTGTACCTGGAG HG1020173N1 NP_075594_1-285_M278N SEQ.ID.NO. 52ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGaacACCTCGCCCCTGTACCTGGAG HG1020171N1 NP_075594_1-285_P275G SEQ.ID.NO. 53ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGATGACCTCGCCCCTGTACCTGGAG HG1020174N1 NP_075594_1-285_P275M_M278N SEQ.ID.NO. 54ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGaacACCTCGCCCCTGTACCTGGAG HG1020176N1 NP_000595_1-372 SEQ.ID.NO. 55ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCC HG1020175N1 NP_000595_1-368SEQ.ID.NO. 56ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTG HG1020177N1 NP_000595_1-367 SEQ.ID.NO. 57ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCA HG1020178N1 NP_000595_1-362 SEQ.ID.NO. 58ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAA GCCCTGHG1020179N1 NP_000595_1-376_D366-D367 SEQ.ID.NO. 59ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGGTGATGACCTCGCCCCTGTACCTGGAGHG1020181N1 NP_000595_1-376_P366M SEQ.ID.NO. 60ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGATGACCTCGCCCCTGTACCTGGAGHG1020182N1 NP_000595_1-376_M369N SEQ.ID.NO. 61ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGaacACCTCGCCCCTGTACCTGGAGHG1020180N1 NP_000595_1-376_P366G SEQ.ID.NO. 62ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGgggGCAGTGATGACCTCGCCCCTGTACCTGGAGHG1020183N1 NP_000595_1-376_P366M_M369N SEQ.ID.NO. 63ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCCGGAAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACagaatgCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGatgGCAGTGaacACCTCGCCCCTGTACCTGGAGHG1020184N1 182571_1-369 SEQ.ID.NO. 64ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGAC HG1020185N1 182571_1-369_17939658_233-464_C237S SEQ.ID.NO. 65ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGACGGATCCGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCT CCGGGTAAAHG1021610N1 182571_1-369_nolinker_17939658_ 233-464_C237S SEQ.ID.NO. 66ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGACGAGCCCAAATCTTCTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACACAGAAGAGCCTCTCCCTGTCTCCGGGT AAAHG1020186N1 13991618_1-159 SEQ.ID.NO. 67ATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGTTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGACHG1020187N1 NP_002002_1-369 SEQ.ID.NO. 68ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGGCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCTCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGAC HG1020188N1 31372_1-369 SEQ.ID.NO. 69ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGAC HG1020189N1 2832350_1-369 SEQ.ID.NO. 70ATGCGGCTGCTGCTGGCCCTGTTGGGGATCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGGCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCTCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGCCAGGTATACGGACHG1021616N1 182571_1-364_17939658_233-464_C237S SEQ.ID.NO. 71ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGCAGCAGCGCCCGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021617N1 182571_1-359_17939658_233-464_C237S SEQ.ID.NO. 72ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGACCCCACATGGACCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021618N1 182571_1-354_17939658_233-464_C237S SEQ.ID.NO. 73ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021619N1 182571_1-352_17939658_233-464_C237SSEQ.ID.NO. 74ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGCCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021620N1 182571_1-351_17939658_233-464_C237SSEQ.ID.NO. 75ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTGTCCCTGGAGGCCTCTGAGGAAGTGGAGCTTGAGCCCTGCCTGGCTCCCAGCCTGGAGCAGCAAGAGCAGGAGCTGACAGTAGCCCTTGGGCAGCCTGTGCGTCTGTGCTGTGGGCGGGCTGAGCGTGGTGGCCACTGGTACAAGGAGGGCAGTCGCCTGGCACCTGCTGGCCGTGTACGGGGCTGGAGGGGCCGCCTAGAGATTGCCAGCTTCCTACCTGAGGATGCTGGCCGCTACCTCTGCCTGGCACGAGGCTCCATGATCGTCCTGCAGAATCTCACCTTGATTACAGGTGACTCCTTGACCTCCAGCAACGATGATGAGGACCCCAAGTCCCATAGGGACCCCTCGAATAGGCACAGTTACCCCCAGCAAGCACCCTACTGGACACACCCCCAGCGCATGGAGAAGAAACTGCATGCAGTACCTGCGGGGAACACCGTCAAGTTCCGCTGTCCAGCTGCAGGCAACCCCACGCCCACCATCCGCTGGCTTAAGGATGGACAGGCCTTTCATGGGGAGAACCGCATTGGAGGCATTCGGCTGCGCCATCAGCACTGGAGTCTCGTGATGGAGAGCGTGGTGCCCTCGGACCGCGGCACATACACCTGCCTGGTAGAGAACGCTGTGGGCAGCATCCGCTATAACTACCTGCTAGATGTGCTGGAGCGGTCCCCGCACCGGCCCATCCTGCAGGCCGGGCTCCCGGCCAACACCACAGCCGTGGTGGGCAGCGACGTGGAGCTGCTGTGCAAGGTGTACAGCGATGCCCAGCCCCACATCCAGTGGCTGAAGCACATCGTCATCAACGGCAGCAGCTTCGGAGCCGACGGTTTCCCCTATGTGCAAGTCCTAAAGACTGCAGACATCAATAGCTCAGAGGTGGAGGTCCTGTACCTGCGGAACGTGTCAGCCGAGGACGCAGGCGAGTACACCTGCCTCGCAGGCAATTCCATCGGCCTCTCCTACCAGTCTGCCTGGCTCACGGTGCTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAAHG1020190N1 NP_056934_1-19 SEQ.ID.NO. 76ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCHG1020191N1 182571_1-19 SEQ.ID.NO. 77ATGCGGCTGCTGCTGGCCCTGTTGGGGGTCCTGCTGAGTGTGCCTGGGCCTCCAGTCHG1020192N1 2832350_1-21 SEQ.ID.NO. 78ATGCGGCTGCTGCTGGCCCTGTTGGGGATCCTGCTGAGTGTGCCTGGGCCTCCAGTCTTG TCCHG1020118N1 linker_sequence SEQ.ID.NO. 79 GGATCCHG1020119N1 17939658_233-464_C237S SEQ.ID.NO. 80GAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020120N1 34528298_241-468SEQ.ID.NO. 81GAGCGCAAATGTTGTGTCGAGTGCCCACCGTGCCCAGCACCACCTGTGGCAGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACGTGCGTGGTGGTGGACGTGAGCCACGAAGACCCCGAGGTCCAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCACGGGAGGAGCAGTTCAACAGCACGTTCCGTGTGGTCAGCGTCCTCACCGTCGTGCACCAGGACTGGCTGAACGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGGCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAACCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTACCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCATGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020121N1 19684073_245-473 SEQ.ID.NO. 82GTCGTGGAGCGGTCCCCTCACCGCCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGATCATCATCTATTGCACAGGGGCCTTCCTCATCTCCTGCATGGTGGGGTCGGTCATCGTCTACAAGATGAAGAGTGGTACCAAGAAGAGTGACTTCCACAGCCAGATGGCTGTGCACAAGCTGGCCAAGAGCATCCCTCTGCGCAGACAGGTAACAGTGTCTGCTGACTCCAGTGCATCCATGAACTCTGGGGTTCTTCTGGTTCGGCCATCACGGCTCTCCTCCAGTGGGACTCCCATGCTAGCAGGGGTCTCTGAGTATGAGCTTCCCGAAGACCCTCGCTGGGAGCTGCCTCGG HG1020374N1 NP_000133_1-375 SEQ.ID.NO. 83ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCHG1020375N1 NP_075254_1-310 SEQ.ID.NO. 84ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAG HG1021603N1 NP_000133_1-375_GS_17939658_233-464_C237S SEQ.ID.NO. 85ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCggatccGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021604N1 NP_000133_1-375_17939658_233-464_C237S SEQ.ID.NO. 86ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021605N1 NP_000133_1-371_17939658_233-464_C237S SEQ.ID.NO. 87ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAAHG1021606N1 NP_000133_1-367_17939658_ 233-464_C237S SEQ.ID.NO. 88ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021607N1 NP_000133_1-366_17939658_ 233-464_C237S SEQ.ID.NO. 89ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021608N1 NP_000133_1-361_17939658_ 233-464_C237S SEQ.ID.NO. 90ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021609N1 NP_000133_1-355_17939658_ 233-464_C237S SEQ.ID.NO. 91ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1020122P1 NP_056934_1-374 SEQ.ID.NO. 92MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLE HG1020123P1 NP_075594_1-285 SEQ.ID.NO. 93MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEHG1020124P1 NP_000595_1-376 SEQ.ID.NO. 94MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLE HG1021602P1 NP_056934_1-374_GS_17939658_ 233-464_C237SSEQ.ID.NO. 95MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKHG1020125P1 NP_056934_1-374_17939658_ 233-464_C237S SEQ.ID.NO. 96MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1020127P1 NP_056934_1-370_17939658_ 233-464_C237S SEQ.ID.NO. 97MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GKHG1020126P1 NP_056934_1-366_17939658_ 233-464_C237S SEQ.ID.NO. 98MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020128P1 NP_056934_1-365_17939658_ 233-464_C237S SEQ.ID.NO. 99MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020129P1 NP_056934_1-360_17939658_ 233-464_C237S SEQ.ID.NO. 100MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020130P1 NP_056934_1-355_17939658_ 233-464_C237S SEQ.ID.NO. 101MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020131P1 NP_056934_1-374_D364-D365_17939658_ 233-464_C237SSEQ.ID.NO. 102MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKHG1020133P1 NP_056934_1-374_P364M_17939658_ 233-464_C237S SEQ.ID.NO. 103MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1020134P1 NP_056934_1-374_M367N_17939658_ 233-464_C237S SEQ.ID.NO. 104MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1020132P1 NP_056934_1-374_P364G_17939658_ 233-464_C237S SEQ.ID.NO. 105MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERGAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1020135P1 NP_056934_1-374_P364M_M367N_ 17939658_233-464_C237SSEQ.ID.NO. 106MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1020136P1 NP_075594_1-285_17939658_ 233-464_C237S SEQ.ID.NO. 107MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020138P1 NP_075594_1-281_17939658_ 233-464_C237S SEQ.ID.NO. 108MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1020137P1 NP_075594_1-277_17939658_233-464_C237S SEQ.ID.NO. 109MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1020139P1 NP_075594_1-276_17939658_233-464_C237S SEQ.ID.NO. 110MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1020140P1 NP_075594_1-271_17939658_233-464_C237S SEQ.ID.NO. 111MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1020141P1 NP_075594_1-285_D275-D276_17939658_233-464_C237S SEQ.ID.NO. 112MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020143P1 NP_075594_1-285_P275M_17939658_ 233-464_C237S SEQ.ID.NO. 113MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020144P1 NP_075594_1-285_M278N_17939658_ 233-464_C237S SEQ.ID.NO. 114MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVNTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020142P1 NP_075594_1-285_P275G_17939658_ 233-464_C237s SEQ.ID.NO. 115MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERGAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020145P1 NP_075594_1-285_P275M_M278N_ 17939658_233-464_C237SSEQ.ID.NO. 116MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020146P1 NP_000595_1-376_17939658_ 233-464_C237S SEQ.ID.NO. 117MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKHG1020148P1 NP_000595_1-372_17939658_ 233-464_C237S SEQ.ID.NO. 118MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSL SPGKHG1020147P1 NP_000595_1-368_17939658_ 233-464_C237S SEQ.ID.NO. 119MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020149P1 NP_000595_1-367_17939658_ 233-464_C237S SEQ.ID.NO. 120MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020150P1 NP_000595_1-362_17939658_ 233-464_C237S SEQ.ID.NO. 121MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020151P1 NP_000595_1-376_D366-D367_17939658_ 233-464_C237SSEQ.ID.NO. 122MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1020153P1 NP_000595_1-376_P366M_17939658_ 233-464_C237S SEQ.ID.NO. 123MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKHG1020154P1 NP_000595_1-376_M369N_17939658_ 233-464_C237S SEQ.ID.NO. 124MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVNTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKHG1020152P1 NP_000595_1-376_P366G_17939658_ 233-464_C237S SEQ.ID.NO. 125MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERGAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKHG1020155P1 NP_000595_1-376_P366M_M369N_ 17939658_233-464_C237SSEQ.ID.NO. 126MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQK SLSLSPGKHG1020157P1 NP_056934_1-370 SEQ.ID.NO. 127MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEAL EERPAVMTSPHG1020156P1 NP_056934_1-366 SEQ.ID.NO. 128MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEAL EERPAVHG1020158P1 NP_056934_1-365 SEQ.ID.NO. 129MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEAL EERPAHG1020159P1 NP_056934_1-360 SEQ.ID.NO. 130MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALHG1020160P1 NP_056934_1-355 SEQ.ID.NO. 131MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTHG1020161P1 NP_056934_1-374_D364-D365 SEQ.ID.NO. 132MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERVMTSPLYLE HG1020163P1 NP_056934_1-374_P364M SEQ.ID.NO. 133MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVMTSPLYLE HG1020164P1 NP_056934_1-374_M367N SEQ.ID.NO. 134MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLE HG1020162P1 NP_056934_1-374_P364G SEQ.ID.NO. 135MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERGAVMTSPLYLE HG1020165P1 NP_056934_1-374_P364M_M367N SEQ.ID.NO. 136MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLE HG1020167P1 NP_075594_1-281 SEQ.ID.NO. 137MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSP HG1020166P1 NP_075594_1-277SEQ.ID.NO. 138MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAV HG1020168P1 NP_075594_1-276SEQ.ID.NO. 139MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPA HG1020169P1 NP_075594_1-271SEQ.ID.NO. 140MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEAL HG1020170P1 NP_075594_1-285_D275-D276SEQ.ID.NO. 141MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERVMTSPLYLEHG1020172P1 NP_075594_1-285_P275M SEQ.ID.NO. 142MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVMTSPLYLEHG1020173P1 NP_075594_1-285_M278N SEQ.ID.NO. 143MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVNTSPLYLEHG1020171P1 NP_075594_1-285_P275G SEQ.ID.NO. 144MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERGAVMTSPLYLEHG1020174P1 NP_075594_1-285_P275M_M278N SEQ.ID.NO. 145MWSWKCLLFWAVLVTATLCTARPSPTLPEQDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLEHG1020176P1 NP_000595_1-372 SEQ.ID.NO. 146MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSP HG1020175P1 NP_000595_1-368 SEQ.ID.NO. 147MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLE ALEERPAVHG1020177P1 NP_000595_1-367 SEQ.ID.NO. 148MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLE ALEERPAHG1020178P1 NP_000595_1-362 SEQ.ID.NO. 149MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLE ALHG1020179P1 NP_000595_1-376_D366-D367 SEQ.ID.NO. 150MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERVMTSPLYLE HG1020181P1 NP_000595_1-376_P366M SEQ.ID.NO. 151MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVMTSPLYLE HG1020182P1 NP_000595_1-376_M369N SEQ.ID.NO. 152MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVNTSPLYLE HG1020180P1 NP_000595_1-376_P366G SEQ.ID.NO. 153MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERGAVMTSPLYLE HG1020183P1 NP_000595_1-376_P366M_M369N SEQ.ID.NO. 154MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNRMPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERMAVNTSPLYLE HG1020184P1 182571_1-369 SEQ.ID.NO. 155MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA AAPEARYTDHG1020185P1 182571_1-369_17939658_233-464_C237S SEQ.ID.NO. 156MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEARYTDGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGKHG1021610P1 182571_1-369_nolinker_17939658_ 233-464_C237S SEQ.ID.NO. 157MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEARYTDEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG KHG1020186P1 13991618_1-159 SEQ.ID.NO. 158MESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEARYTD HG1020187P1 NP_002002_1-369SEQ.ID.NO. 159MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDLSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA AAPEARYTDHG1020188P1 31372_1-369 SEQ.ID.NO. 160MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGAVGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA AAPEARYTDHG1020189P1 2832350_1-369 SEQ.ID.NO. 161MRLLLALLGILLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDLSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTA AAPEARYTDHG1021616P1 182571_1-364_17939658_233-464_C237S SEQ.ID.NO. 162MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTAAAPEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021617P1 182571_1-359_17939658_233-464_C237S SEQ.ID.NO. 163MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEDPTWTEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021618P1 182571_1-354_17939658_233-464_C237S SEQ.ID.NO. 164MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021619P1 182571_1-352_17939658_233-464_C237S SEQ.ID.NO. 165MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021620P1 182571_1-351_17939658_233-464_C237S SEQ.ID.NO. 166MRLLLALLGVLLSVPGPPVLSLEASEEVELEPCLAPSLEQQEQELTVALGQPVRLCCGRAERGGHWYKEGSRLAPAGRVRGWRGRLEIASFLPEDAGRYLCLARGSMIVLQNLTLITGDSLTSSNDDEDPKSHRDPSNRHSYPQQAPYWTHPQRMEKKLHAVPAGNTVKFRCPAAGNPTPTIRWLKDGQAFHGENRIGGIRLRHQHWSLVMESVVPSDRGTYTCLVENAVGSIRYNYLLDVLERSPHRPILQAGLPANTTAVVGSDVELLCKVYSDAQPHIQWLKHIVINGSSFGADGFPYVQVLKTADINSSEVEVLYLRNVSAEDAGEYTCLAGNSIGLSYQSAWLTVLEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1020190P1 NP_056934_1-19SEQ.ID.NO. 167 MWSWKCLLFWAVLVTATLC HG1020191P1 182571_1-19SEQ.ID.NO. 168 MRLLLALLGVLLSVPGPPV HG1020192P1 2832350_1-21SEQ.ID.NO. 169 MRLLLALLGILLSVPGPPVLS HG1020118P1 linker_sequenceSEQ.ID.NO. 170 GS HG1020119P1 17939658_233-464_C237S SEQ.ID.NO. 171EPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020120P1 34528298_241-468 SEQ.ID.NO. 172ERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1020121P1 19684073_245-473 SEQ.ID.NO. 173ESKYGPPCPSCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGKHG1020374P1 NP_000133_1-375 SEQ.ID.NO. 174MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAG HG1020375P1 NP_075254_1-310 SEQ.ID.NO. 175MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGP DGTPYVTVLKHG1021603P1 NP_000133_1-375_GS_17939658_ 233-464_C237S SEQ.ID.NO. 176MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAGGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGKHG1021604P1 NP_000133_1-375_17939658_ 233-464_C237S SEQ.ID.NO. 177MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKHG1021605P1 NP_000133_1-371_17939658_ 233-464_C237S SEQ.ID.NO. 178MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGKHG1021606P1 NP_000133_1-367_17939658_ 233-464_C237S SEQ.ID.NO. 179MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021607P1 NP_000133_1-366_17939658_ 233-464_C237S SEQ.ID.NO. 180MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021608P1 NP_000133_1-361_17939658_ 233-464_C237S SEQ.ID.NO. 181MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021609P1 NP_000133_1-355_17939658_ 233-464_C237S SEQ.ID.NO. 182MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021621N1 NP_056934_1-374 SEQ.ID.NO. 183ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGHG1021622N1 FGFR1IIIb_1-374_17939658_ 233-464_C237S SEQ.ID.NO. 184ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCCTGTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021623N1 FGFR1IIIb_1-370_17939658_ 233-464_C237SSEQ.ID.NO. 185ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGATGACCTCGCCCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAAHG1021624N1 FGFR1IIIb_1-366_17939658_ 233-464_C237S SEQ.ID.NO. 186ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021625N1 FGFR1IIIb_1-365_17939658_ 233-464_C237S SEQ.ID.NO. 187ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAAGAGAGGCCGGCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021626N1 FGFR1IIIb_1-360_17939658_ 233-464_C237S SEQ.ID.NO. 188ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGTTCTGGAAGCCCTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021627N1 FGFR1IIIb_1-355_17939658_ 233-464_C237S SEQ.ID.NO. 189ATGTGGAGCTGGAAGTGCCTCCTCTTCTGGGCTGTGCTGGTCACAGCCACACTCTGCACCGCTAGGCCGTCCCCGACCTTGCCTGAACAAGCCCAGCCCTGGGGAGCCCCTGTGGAAGTGGAGTCCTTCCTGGTCCACCCCGGTGACCTGCTGCAGCTTCGCTGTCGGCTGCGGGACGATGTGCAGAGCATCAACTGGCTGCGGGACGGGGTGCAGCTGGCGGAAAGCAACCGCACCCGCATCACAGGGGAGGAGGTGGAGGTGCAGGACTCCGTGCCCGCAGACTCCGGCCTCTATGCTTGCGTAACCAGCAGCCCCTCGGGCAGTGACACCACCTACTTCTCCGTCAATGTTTCAGATGCTCTCCCCTCCTCGGAGGATGATGATGATGATGATGACTCCTCTTCAGAGGAGAAAGAAACAGATAACACCAAACCAAACCCCGTAGCTCCATATTGGACATCCCCAGAAAAGATGGAAAAGAAATTGCATGCAGTGCCGGCTGCCAAGACAGTGAAGTTCAAATGCCCTTCCAGTGGGACCCCAAACCCCACACTGCGCTGGTTGAAAAATGGCAAAGAATTCAAACCTGACCACAGAATTGGAGGCTACAAGGTCCGTTATGCCACCTGGAGCATCATAATGGACTCTGTGGTGCCCTCTGACAAGGGCAACTACACCTGCATTGTGGAGAATGAGTACGGCAGCATCAACCACACATACCAGCTGGATGTCGTGGAGCGGTCCCCTCACCGGCCCATCCTGCAAGCAGGGTTGCCCGCCAACAAAACAGTGGCCCTGGGTAGCAACGTGGAGTTCATGTGTAAGGTGTACAGTGACCCGCAGCCGCACATCCAGTGGCTAAAGCACATCGAGGTGAATGGGAGCAAGATTGGCCCAGACAACCTGCCTTATGTCCAGATCTTGAAGACTGCTGGAGTTAATACCACCGACAAAGAGATGGAGGTGCTTCACTTAAGAAATGTCTCCTTTGAGGACGCAGGGGAGTATACGTGCTTGGCGGGTAACTCTATCGGACTCTCCCATCACTCTGCATGGTTGACCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021628N1 P22607_1-375 SEQ.ID.NO. 190ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCHG1021629N1 P22607_1-375_17939658_ 233-464_C237S SEQ.ID.NO. 191ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGTGTATGCAGGCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021630N1 P22607_1-371_17939658_233-464_C237SSEQ.ID.NO. 192ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGGCGGGCAGTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCT CCGGGTAAAHG1021631N1 P22607_1-367_17939658_233-464_C237S SEQ.ID.NO. 193ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGACGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021632N1 P22607_1-366_17939658_233-464_C237S SEQ.ID.NO. 194ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCTGGTGGAGGCTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021633N1 P22607_1-361_17939658_233-464_C237S SEQ.ID.NO. 195ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGTGCTGCCAGCCGAGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021634N1 P22607_1-355_17939658_233-464_C237S SEQ.ID.NO. 196ATGGGCGCCCCTGCCTGCGCCCTCGCGCTCTGCGTGGCCGTGGCCATCGTGGCCGGCGCCTCCTCGGAGTCCTTGGGGACGGAGCAGCGCGTCGTGGGGCGAGCGGCAGAAGTCCCGGGCCCAGAGCCCGGCCAGCAGGAGCAGTTGGTCTTCGGCAGCGGGGATGCTGTGGAGCTGAGCTGTCCCCCGCCCGGGGGTGGTCCCATGGGGCCCACTGTCTGGGTCAAGGATGGCACAGGGCTGGTGCCCTCGGAGCGTGTCCTGGTGGGGCCCCAGCGGCTGCAGGTGCTGAATGCCTCCCACGAGGACTCCGGGGCCTACAGCTGCCGGCAGCGGCTCACGCAGCGCGTACTGTGCCACTTCAGTGTGCGGGTGACAGACGCTCCATCCTCGGGAGATGACGAAGACGGGGAGGACGAGGCTGAGGACACAGGTGTGGACACAGGGGCCCCTTACTGGACACGGCCCGAGCGGATGGACAAGAAGCTGCTGGCCGTGCCGGCCGCCAACACCGTCCGCTTCCGCTGCCCAGCCGCTGGCAACCCCACTCCCTCCATCTCCTGGCTGAAGAACGGCAGGGAGTTCCGCGGCGAGCACCGCATTGGAGGCATCAAGCTGCGGCATCAGCAGTGGAGCCTGGTCATGGAAAGCGTGGTGCCCTCGGACCGCGGCAACTACACCTGCGTCGTGGAGAACAAGTTTGGCAGCATCCGGCAGACGTACACGCTGGACGTGCTGGAGCGCTCCCCGCACCGGCCCATCCTGCAGGCGGGGCTGCCGGCCAACCAGACGGCGGTGCTGGGCAGCGACGTGGAGTTCCACTGCAAGGTGTACAGTGACGCACAGCCCCACATCCAGTGGCTCAAGCACGTGGAGGTGAACGGCAGCAAGGTGGGCCCGGACGGCACACCCTACGTTACCGTGCTCAAGACGGCGGGCGCTAACACCACCGACAAGGAGCTAGAGGTTCTCTCCTTGCACAACGTCACCTTTGAGGACGCCGGGGAGTACACCTGCCTGGCGGGCAATTCTATTGGGTTTTCTCATCACTCTGCGTGGCTGGTGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021621P1 NP_056934_1-374 SEQ.ID.NO. 197MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLE HG1021622P1 FGFR1IIIb_1-374_17939658_233-464_C237SSEQ.ID.NO. 198MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPLYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1021623P1 FGFR1IIIb_1-370_17939658_233-464_C237S SEQ.ID.NO. 199MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVMTSPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GKHG1021624P1 FGFR1IIIb_1-366_17939658_233-464_C237S SEQ.ID.NO. 200MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021625P1 FGFR1IIIb_1-365_17939658_233-464_C237S SEQ.ID.NO. 201MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEERPAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021626P1 FGFR1IIIb_1-360_17939658_233-464_C237S SEQ.ID.NO. 202MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTVLEALEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021627P1 FGFR1IIIb_1-355_17939658_233-464_C237S SEQ.ID.NO. 203MWSWKCLLFWAVLVTATLCTARPSPTLPEQAQPWGAPVEVESFLVHPGDLLQLRCRLRDDVQSINWLRDGVQLAESNRTRITGEEVEVQDSVPADSGLYACVTSSPSGSDTTYFSVNVSDALPSSEDDDDDDDSSSEEKETDNTKPNPVAPYWTSPEKMEKKLHAVPAAKTVKFKCPSSGTPNPTLRWLKNGKEFKPDHRIGGYKVRYATWSIIMDSVVPSDKGNYTCIVENEYGSINHTYQLDVVERSPHRPILQAGLPANKTVALGSNVEFMCKVYSDPQPHIQWLKHIEVNGSKIGPDNLPYVQILKTAGVNTTDKEMEVLHLRNVSFEDAGEYTCLAGNSIGLSHHSAWLTEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1021628P1 P22607_1-375SEQ.ID.NO. 204MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAG HG1021629P1 P22607_1-375_17939658_233-464_C237SSEQ.ID.NO. 205MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSVYAGEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKS LSLSPGKHG1021630P1 P22607_1-371_17939658_233-464_C2375 SEQ.ID.NO. 206MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEAGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLS PGKHG1021631P1 P22607_1-367_17939658_233-464_C237S SEQ.ID.NO. 207MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEADEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021632P1 P22607_1-366_17939658_233-464_C237S SEQ.ID.NO. 208MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEELVEAEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021633P1 P22607_1-361_17939658_233-464_C237S SEQ.ID.NO. 209MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVVLPAEEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021634P1 P22607_1-355_17939658_233-464_C237S SEQ.ID.NO. 210MGAPACALALCVAVAIVAGASSESLGTEQRVVGRAAEVPGPEPGQQEQLVFGSGDAVELSCPPPGGGPMGPTVWVKDGTGLVPSERVLVGPQRLQVLNASHEDSGAYSCRQRLTQRVLCHFSVRVTDAPSSGDDEDGEDEAEDTGVDTGAPYWTRPERMDKKLLAVPAANTVRFRCPAAGNPTPSISWLKNGREFRGEHRIGGIKLRHQQWSLVMESVVPSDRGNYTCVVENKFGSIRQTYTLDVLERSPHRPILQAGLPANQTAVLGSDVEFHCKVYSDAQPHIQWLKHVEVNGSKVGPDGTPYVTVLKTAGANTTDKELEVLSLHNVTFEDAGEYTCLAGNSIGFSHHSAWLVEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021635N1 15281415_1-378 SEQ.ID.NO. 211ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGHG1021636N1 15281415_1-378_17939658_233-464_C237S SEQ.ID.NO. 212ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021637N1 15281415_1-378_GS_17939658233-464_C237S SEQ.ID.NO. 213ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGGGATCCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021638N1 15281415_1-374_17939658_233-464_C237S SEQ.ID.NO. 214ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021639N1 15281415_1-370_17939658_233-464_C237SSEQ.ID.NO. 215ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGGAAGAGAAAAGGAGATTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCG GGTAAAHG1021640N1 15281415_1-369_17939658_233-464_C237S SEQ.ID.NO. 216ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGGAAGAGAAAAGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAAHG1021641N1 15281415_1-364_17939658_233-464_C237S SEQ.ID.NO. 217ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGTCCTGCCAAAACAGCAAGCGCCTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021642N1 15281415_1-356_17939658_233-464_C237S SEQ.ID.NO. 218ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGCACTCGGGGATAAATAGTTCCAATGCAGAAGTGCTGGCTCTGTTCAATGTGACCGAGGCGGATGCTGGGGAATATATATGTAAGGTCTCCAATTATATAGGGCAGGCCAACCAGTCTGCCTGGCTCACTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021643N1 NP_000132_1-377 SEQ.ID.NO. 219ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGHG1021644N1 NP_000132_1-377_17939658_233-464_C237S SEQ.ID.NO. 220ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021645N1 NP_000132_1-377_GS_17939658_233-464_C237S SEQ.ID.NO. 221ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGACTACCTGGAGGGATCCGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021646N1 NP_000132_1-373_17939658_233-464_C237S SEQ.ID.NO. 222ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGATTACAGCTTCCCCAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021647N1 NP_000132_1-369_17939658_ 233-464_C237SSEQ.ID.NO. 223ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGATTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGT AAAHG1021648N1 NP_000132_1-368_17939658_ 233-464_C237S SEQ.ID.NO. 224ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGGAAGAGAAAAGGAGGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021649N1 NP_000132_1-363_17939658_ 233-464_C237S SEQ.ID.NO. 225ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGTTCTGCCAGCGCCTGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAAHG1021650N1 NP_000132_1-358_17939658_ 233-464_C237S SEQ.ID.NO. 226ATGGTCAGCTGGGGTCGTTTCATCTGCCTGGTCGTGGTCACCATGGCAACCTTGTCCCTGGCCCGGCCCTCCTTCAGTTTAGTTGAGGATACCACATTAGAGCCAGAAGAGCCACCAACCAAATACCAAATCTCTCAACCAGAAGTGTACGTGGCTGCGCCAGGGGAGTCGCTAGAGGTGCGCTGCCTGTTGAAAGATGCCGCCGTGATCAGTTGGACTAAGGATGGGGTGCACTTGGGGCCCAACAATAGGACAGTGCTTATTGGGGAGTACTTGCAGATAAAGGGCGCCACGCCTAGAGACTCCGGCCTCTATGCTTGTACTGCCAGTAGGACTGTAGACAGTGAAACTTGGTACTTCATGGTGAATGTCACAGATGCCATCTCATCCGGAGATGATGAGGATGACACCGATGGTGCGGAAGATTTTGTCAGTGAGAACAGTAACAACAAGAGAGCACCATACTGGACCAACACAGAAAAGATGGAAAAGCGGCTCCATGCTGTGCCTGCGGCCAACACTGTCAAGTTTCGCTGCCCAGCCGGGGGGAACCCAATGCCAACCATGCGGTGGCTGAAAAACGGGAAGGAGTTTAAGCAGGAGCATCGCATTGGAGGCTACAAGGTACGAAACCAGCACTGGAGCCTCATTATGGAAAGTGTGGTCCCATCTGACAAGGGAAATTATACCTGTGTGGTGGAGAATGAATACGGGTCCATCAATCACACGTACCACCTGGATGTTGTGGAGCGATCGCCTCACCGGCCCATCCTCCAAGCCGGACTGCCGGCAAATGCCTCCACAGTGGTCGGAGGAGACGTAGAGTTTGTCTGCAAGGTTTACAGTGATGCCCAGCCCCACATCCAGTGGATCAAGCACGTGGAAAAGAACGGCAGTAAATACGGGCCCGACGGGCTGCCCTACCTCAAGGTTCTCAAGGCCGCCGGTGTTAACACCACGGACAAAGAGATTGAGGTTCTCTATATTCGGAATGTAACTTTTGAGGACGCTGGGGAATATACGTGCTTGGCGGGTAATTCTATTGGGATATCCTTTCACTCTGCATGGTTGACAGAGCCCAAATCTtctGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA HG1021635P1 15281415_1-378 SEQ.ID.NO. 227MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEITASPDYLE HG1021636P1 15281415_1-378_17939658_ 233-464_C237SSEQ.ID.NO. 228MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEITASPDYLE HG1021637P1 15281415_1-378_GS_17939658_ 233-464_C237SSEQ.ID.NO. 229MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEITASPDYLEGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK HG1021638P1 15281415_1-374_17939658_ 233-464_C237SSEQ.ID.NO. 230MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEITASPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSL SLSPGKHG1021639P1 15281415_1-370_17939658_ 233-464_C237S SEQ.ID.NO. 231MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEIEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSP GKHG1021640P1 15281415_1-369_17939658_ 233-464_C237S SEQ.ID.NO. 232MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPGREKEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG KHG1021641P1 15281415_1-364_17939658_ 233-464_C237S SEQ.ID.NO. 233MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTVLPKQQAPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021642P1 15281415_1-356_17939658_ 233-464_C237S SEQ.ID.NO. 234MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKHSGINSSNAEVLALFNVTEADAGEYICKVSNYIGQANQSAWLTEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021643P1 NP_000132_1-377 SEQ.ID.NO. 235MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEITASPDYLE HG1021644P1 NP_000132_1-377_17939658_ 233-464_C237SSEQ.ID.NO. 236MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEITASPDYLEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQ KSLSLSPGKHG1021645P1 NP_000132_1-377_GS_17939658_ 233-464_C237S SEQ.ID.NO. 237MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEITASPDYLEGSEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHY TQKSLSLSPGKHG1021646P1 NP_000132_1-373_17939658_ 233-464_C237S SEQ.ID.NO. 238MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEITASPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLS LSPGKHG1021647P1 NP_000132_1-369_17939658_ 233-464_C237S SEQ.ID.NO. 239MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEIEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG KHG1021648P NP_000132_1-368_17939658_233-464_C237S SEQ.ID.NO. 240MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPGREKEEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021649P1 NP_000132_1-363_17939658_ 233-464_C237S SEQ.ID.NO. 241MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTVLPAPEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021650P1 NP_000132_1-358_17939658_ 233-464_C237S SEQ.ID.NO. 242MVSWGRFICLVVVTMATLSLARPSFSLVEDTTLEPEEPPTKYQISQPEVYVAAPGESLEVRCLLKDAAVISWTKDGVHLGPNNRTVLIGEYLQIKGATPRDSGLYACTASRTVDSETWYFMVNVTDAISSGDDEDDTDGAEDFVSENSNNKRAPYWTNTEKMEKRLHAVPAANTVKFRCPAGGNPMPTMRWLKNGKEFKQEHRIGGYKVRNQHWSLIMESVVPSDKGNYTCVVENEYGSINHTYHLDVVERSPHRPILQAGLPANASTVVGGDVEFVCKVYSDAQPHIQWIKHVEKNGSKYGPDGLPYLKVLKAAGVNTTDKEIEVLYIRNVTFEDAGEYTCLAGNSIGISFHSAWLTEPKSSDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKHG1021651P1 R1_delfragment_1 SEQ.ID.NO. 243 LYLEHG1021652P1 R1_delfragment_2 SEQ.ID.NO. 244 PLYLEHG1021653P1 R1_delfragment_3 SEQ.ID.NO. 245 MTSPLYLEHG1021654P1 R1_delfragment_4 SEQ.ID.NO. 246 AVMTSPLYLEHG1021655P1 R1_delfragment_5 SEQ.ID.NO. 247 VMTSPLYLEHG1021656P1 R1_delfragment_6 SEQ.ID.NO. 248 EERPAVMTSPLYLEHG1021657P1 R1_delfragment_7 SEQ.ID.NO. 249 LEERPAVMTSPLYLEHG1021658P1 R1_delfragment_8 SEQ.ID.NO. 250 KALEERPAVMTSPLYLEHG1021659P1 R1_delfragment_9 SEQ.ID.NO. 251 EALEERPAVMTSPLYLEHG1021660P1 R1_delfragment_10 SEQ.ID.NO. 252 RPVAKALEERPAVMTSPLYLEHG1021661P1 R2_delfragment_1 SEQ.ID.NO. 253 DYLEHG1021662P1 R2_delfragment_2 SEQ.ID.NO. 254 PDYLEHG1021663P1 R2_delfragment_3 SEQ.ID.NO. 255 TASPDYLEHG1021664P1 R2_delfragment_4 SEQ.ID.NO. 256 ITASPDYLEHG1021665P1 R2_delfragment_5 SEQ.ID.NO. 257 EITASPDYLEHG1021666P1 R2_delfragment_6 SEQ.ID.NO. 258 GREKEITASPDYLEHG1021667P1 R2_delfragment_7 SEQ.ID.NO. 259 PGREKEITASPDYLEHG1021668P1 R2_delfragment_8 SEQ.ID.NO. 260 APGREKEITASPDYLEHG1021669P1 R2_delfragment_9 SEQ.ID.NO. 261 PAPGREKEITASPDYLEHG1021670P1 R2_delfragment_10 SEQ.ID.NO. 262 QAPGREKEITASPDYLEHG1021671P1 R2_delfragment_11 SEQ.ID.NO. 263 PKQQAPGREKEITASPDYLEHG1021672P1 R3_delfragment_1 SEQ.ID.NO. 264 VYAGHG1021673P1 R3_delfragment_2 SEQ.ID.NO. 265 SVYAGHG1021674P1 R3_delfragment_3 SEQ.ID.NO. 266 EAGSVYAGHG1021675P1 R3_delfragment_4 SEQ.ID.NO. 267 DEAGSVYAGHG1021676P1 R3_delfragment_5 SEQ.ID.NO. 268 ADEAGSVYAGHG1021677P1 R3_delfragment_6 SEQ.ID.NO. 269 ELVEADEAGSVYAGHG1021678P1 R3_delfragment_7 SEQ.ID.NO. 270 EELVEADEAGSVYAGHG1021679P1 R3_delfragment_8 SEQ.ID.NO. 271 AEEELVEADEAGSVYAGHG1021680P1 R3_delfragment_9 SEQ.ID.NO. 272 PAEEELVEADEAGSVYAGHG1021681P1 R3_delfragment_10 SEQ.ID.NO. 273 GPRAAEEELVEADEAGSVYAGHG1021682P1 R4_delfragment_1 SEQ.ID.NO. 274 RYTDHG1021683P1 R4_delfragment_2 SEQ.ID.NO. 275 ARYTDHG1021684P1 R4_delfragment_3 SEQ.ID.NO. 276 APEARYTDHG1021685P1 R4_delfragment_4 SEQ.ID.NO. 277 AAPEARYTDHG1021686P1 R4_delfragment_5 SEQ.ID.NO. 278 AAAPEARYTDHG1021687P1 R4_delfragment_6 SEQ.ID.NO. 279 PTWTAAAPEARYTDHG1021688P1 R4_delfragment_7 SEQ.ID.NO. 280 DPTWTAAAPEARYTDHG1021689P1 R4_delfragment_8 SEQ.ID.NO. 281 EEDPTWTAAAPEARYTDHG1021690P1 R4_delfragment_9 SEQ.ID.NO. 282 PEEDPTWTAAAPEARYTD

1. An FGFR fusion protein comprising a first polypeptide that comprisesan extracellular domain of an FGFR polypeptide and a fusion partner,wherein the extracellular domain comprises a C-terminus, wherein theC-terminus comprises a variant of a wildtype FGFR extracellular domainC-terminus, wherein the variant comprises a deletion of 1-22 amino acidresidues present in a wildtype FGFR1, FGFR2, FGFR3, or FGFR4extracellular domain C-terminus, and wherein the FGFR fusion proteinbinds at least one FGF ligand or a biologically active fragment thereof.